Tetracyclic derivative inhibitors, methods of making and using same

Abstract

Inhibitors of tetranor derivatives, methods of making and uses thereof. In particular, tetranor derivative compounds, methods of making and pharmaceutical compositions containing the compounds, and uses thereof in the treatment of cancer.

Description

Tetracycline derivative inhibitors, preparation methods and applications thereof Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a tetracycline derivative inhibitor, a preparation method and an application thereof. Background Art

[0002] Protein arginase methyltransferases (PRMTs) are divided into three major categories based on catalytic activity and product type: types I, II, and III. Type I primarily includes PRMT1 / 2 / 3 / 4 / 6 / 8, which catalyze the formation of asymmetric dimethylarginine (ADMA) from substrates; type II includes PRMT5 / 9, which catalyze the formation of symmetric dimethylarginine (SDMA) from substrates; and type III, which only includes PRMT7, is responsible for catalyzing the formation of monomethylarginine (MMA) from substrates. PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer methyl groups to substrates such as DNA, RNA, and histones. Arginine residues on the substrates undergo symmetrical dimethylation to form SDMA, which regulates multiple key cellular processes, including transcription, translation, and DNA repair, maintaining cellular homeostasis. It also participates in regulating tumor cell growth and survival pathways and promotes tumorigenesis and progression. Elevated PRMT5 expression has also been shown to be associated with poor prognosis in various cancers, making it a highly promising epigenetic target.

[0003] Methylthioadenosine phosphorylase (MTAP) catalyzes the conversion of methylthioadenosine (MTA) to methionine, which is essential for maintaining normal cellular function. Loss of the MTAP gene leads to intracellular accumulation of MTA. MTA competes with the PRMT5 substrate SAM, reducing PRMT5 activity and generating a large number of PRMT5-MTA complexes. Loss of the MTAP gene increases tumor dependence on PRMT5. Inhibiting PRMT5 can lead to a "synthetic lethality" effect in MTAP-deficient tumors. PARP inhibitors, based on this "synthetic lethality" theory, have achieved significant success in precision medicine for oncology. The MTAP gene is adjacent to the most common tumor suppressor gene in human cancers, CDKN2A, and is frequently co-deleted with CDKN2A. This co-deletion occurs in 10%-15% of all cancers, primarily in non-small cell lung cancer (12%-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), suggesting significant market potential.

[0004] Currently, there are no PRMT5 inhibitors on the market. Early PRMT5 inhibitors were non-selective, substrate-competitive inhibitors of SAM, which resulted in severe hematologic side effects and a narrow safety window. First-generation PRMT5 inhibitors GSK-3326595, JNJ-64619178, and PF-06939999 have made poor clinical progress. A new generation of PRMT5 inhibitors targeting the PRMT5-MTA complex is only effective against tumors with MTAP deficiency and MTA enrichment, with high selectivity for wild-type MTAP. This mechanistically reduces hematologic toxicity and has been validated in preclinical studies, potentially significantly increasing the safety window.

[0005] This patent relates to a novel, selective PRMT5-MTA inhibitor that is active only against MTAP-deficient cells and exhibits minimal inhibition against wild-type MTAP cells. This approach avoids the hematologic toxicity and other side effects associated with clinically unselective PRMT5 inhibitors. As a novel PRMT5-MTA inhibitor, the highly selective PRMT5-MTA inhibitor can be used to treat various tumors, cancers, and other diseases. Summary of the Invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0007] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C;

[0008] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0009] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Condensed cycloalkyl, 6-10 membered condensed heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0010] L1 is selected from a bond, -(CR aa Rbb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O)-、-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents in aryl and 5-12 membered heteroaryl; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0011] L2 is selected from a bond, -(CRaa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-12 Aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR f ) or -P(O)Re R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-10 Aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -OR e 、-NR e R f、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0013] Or, R1 and R a 、R b or R c Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0014] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0015] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h 、-C(=NR i )NR g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f Preferably, the alkyl group is substituted by one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0016] Alternatively, any two R3 atoms are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 4-alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0017] R a 、R b 、R c 、R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0018] or R a With R b Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0019] Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2-6 Alkenylene or C 2-6 Alkynylidene, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0020] R g 、R h 、R i and R j are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0021] R aa 、R bb 、R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1- 6-hydroxyalkyl, cyano-substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1- 3 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0022] R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0023] R gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0024] x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0025] m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and

[0026] n2 is selected from 0, 1, 2, 3 or 4.

[0027] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that Selected from

[0028] The present invention also provides a compound represented by general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0029] M1 is selected from -N- or -CR a -;M a Selected from CR 2a NR 2a or N; M b Selected from CR 2b NR 2b or N;

[0030] Or, R 2a With R 2b Linked to form ring A;

[0031] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R 2c replaced by;

[0032] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0033] L2 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -;

[0034] L5 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NRN -、-NR N S(O)2-, =CR 9a R 9b 、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0035] L6 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N-、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b 、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0036] L7 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10-、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b 、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0037] R 2a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0038] R 2b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0039] R 2c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0040] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0041] R 9a and R 9b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0042] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0043] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0044] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0045] R g and R h are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0046] R N Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0047] R aa 、R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0048] R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0049] y is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; n2 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2, 3 or 4; n9 is selected from 0, 1, 2, 3 or 4; n10 is selected from 0, 1, 2, 3 or 4.

[0050] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (III-E):

[0051] L5 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C(=CR 9a R 9b ), C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from bond, -O-, -S-, -C(O), -NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6- 12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0052] L6 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b )n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C(=CR 9a R 9b ), C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from bond, -O-, -S-, -C(O), -NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6- 12Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0053] L7 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C(=CR 9a R 9b ), C 1-6 Alkylene, C 2-6 Alkenylene, C2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from bond, -O-, -S-, -C(O), -NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6- 12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0054] Ring A, Ring B, L2, M1, M3, R c , R2, R3, x and y are as defined in any of the above embodiments.

[0055] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (IV-E):

[0056] M5 is selected from N or CR 3a ; M6 is selected from N or CR 3b ;

[0057] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0058] R 3a 、R 3b 、R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1- 6 alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0059] R 3c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0060] Ring A, M1, M3, R c , R2, x, L5, L6, L7, n8 and n9 are as defined in any of the above embodiments.

[0061] In a preferred embodiment of the present invention, Ring A is selected from a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl; preferably a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 5-membered heteroaryl or a 6-membered heteroaryl; more preferably More preferred

[0062] In a preferred embodiment of the present invention, ring B is selected from 3-6 membered heterocyclyl and phenyl or 3-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably

[0063] In a preferred embodiment of the present invention, ring B is selected from 6-14 membered tricyclic heterocyclic group; preferably 6-14 membered tricyclic spiro heterocyclic group or 6-14 membered tricyclic fused heterocyclic group; more preferably

[0064] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (VI-A) or (VI-B):

[0065] n11 is selected from 0, 1 or 2; M5 is selected from N or CR 3a ; M6 is selected from N or CR 3b ;

[0066] R 3a 、R 3b 、R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1- 6 alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0067] R 3c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents.

[0068] In a preferred embodiment of the present invention, L6 is selected from -O-, -S-, -C(O), -NR N -、C 1-3 Alkylene or C 2- 4 alkenylene, the C 1-3 Alkylene and C 2-4 Alkenylene, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0069] In a preferred embodiment of the present invention, n8 is selected from 1, 2 or 3; n9 is selected from 0, 1 or 2.

[0070] In a preferred embodiment of the present invention, R2 or R 2c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with halogenated alkyl or cyano 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with halogenated alkyl or cyano 1-3 Alkyl and C 3-8 Cycloalkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with halogenated alkyl or cyano 1-3 Alkyl and C 3-8 substituted by one or more substituents in the cycloalkyl group;

[0071] R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 alkyl;

[0072] Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl,

[0073] In a preferred embodiment of the present invention, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl.

[0074] In a preferred embodiment of the present invention, R cSelected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl.

[0075] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that R3 and R 3c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or -SF5, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2- 6 alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0076] R 3a 、R 3b 、R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0077] The present invention also provides a compound represented by the general formula (AI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0078] R' is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy or C 1-6 hydroxyalkyl;

[0079] R is selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or

[0080] R" is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0081] The compound represented by the following general formula (A-II) is preferred:

[0082] Preferably, the compound represented by general formula (A-II) is further represented by general formula (IV-EI), general formula (IV-AI) or general formula (IV-BI):

[0083] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0084] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0085] M1, M a 、M b , Ring A, Ring B, L2, L5, L6, L7, R a 、R b 、R c 、R3、M5、M6、R 3a 、R 3b 、R 3c 、R 3d 、R 3e , R5, n11, n8, n9, x and y are as defined in any of the above embodiments.

[0086] The present invention also provides a method for preparing the compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that:

[0087] The compound represented by general formula (AI) reacts in the presence of a condensing agent and a base to obtain a compound represented by general formula (A-II), and further removes the protecting group to obtain a compound represented by general formula (A);

[0088] Preferably, the method is a method for preparing a compound represented by general formula (IV-E), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0089] The compound represented by the general formula (IV-EI) reacts in the presence of a condensing agent and a base to obtain a compound represented by the general formula (IV-E-II), and the protecting group is further removed to obtain a compound represented by the general formula (IV-E);

[0090] Alternatively, the method is a method for preparing a compound represented by general formula (VI-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0091] The compound represented by the general formula (VI-AI) reacts in the presence of a condensing agent and a base to obtain a compound represented by the general formula (VI-A-II), and the protecting group is further removed to obtain a compound represented by the general formula (VI-A);

[0092] Alternatively, the method is a method for preparing a compound represented by general formula (VI-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0093] The compound represented by the general formula (VI-BI) reacts in the presence of a condensing agent and a base to obtain a compound represented by the general formula (VI-B-II), and the protecting group is further removed to obtain a compound represented by the general formula (VI-B);

[0094] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0095] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0096] M1, M a 、M b , Ring A, Ring B, L2, L5, L6, L7, R a 、R b 、R c 、R3、M5、M6、R3a 、R 3b 、R 3c 、R 3d 、R 3e , R5, n11, n8, n9, x and y are as described in any of the above embodiments.

[0097] In a preferred embodiment of the present invention, the condensing agent in the preparation method is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate.

[0098] The base is selected from potassium carbonate, methylamine, triethylamine, diisopropylamine, pyridine, imidazole, N-methylimidazole or N-methylmorpholine.

[0099] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of the embodiments, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0100] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of PRMT5 inhibitor drugs.

[0101] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer; preferably, the cancer is a cancer with MTAP gene deletion.

[0102] The present invention further relates to a method for preparing a method for treating cancer using the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition; preferably, the cancer is selected from cancers with MTAP gene deletion.

[0103] In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0104] The present invention also relates to a method for preventing and / or treating cancer, comprising administering to a patient a therapeutically effective dose of a compound shown in any embodiment, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0105] The present invention also relates to a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0106] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60% or 50%.

[0107] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0108] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0109] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0110] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0111] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0112] In some embodiments, the present method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer, or bile duct cancer.

[0113] In some embodiments, the lung cancer is selected from non-small cell lung cancer, lung squamous cell carcinoma, or lung adenocarcinoma; and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0114] Detailed Description of the Invention

[0115] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0116] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0117] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0118] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is an unsaturated aliphatic hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0119] The term "alkenylene" refers to an alkenyl group in which one hydrogen atom is further substituted, wherein "alkenyl" is as defined above. In one embodiment, the alkenylene group is an optionally substituted alkyl group as described elsewhere herein.

[0120] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8) or 3 to 6 (C 3-6 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0121] The term "alkynylene" refers to an alkynyl group in which one hydrogen atom is further substituted, wherein "alkynyl" is as defined above. In one embodiment, the alkynylene group is an optionally substituted alkyl group as described elsewhere herein.

[0122] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0123] The term "spiroalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroalkyl group contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10) (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl is divided into mono-, di-, or poly-spirocycloalkyl according to the number of shared spiro atoms between the rings, and in one embodiment, is mono- and di-spirocycloalkyl. In one embodiment, it is a 4-, 3-, 5-, 4-, 5-, 4-, 6-, 5-, or 5-membered mono-spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0124] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the fused cycloalkyl group comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7- 10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and in one embodiment, it is bicyclic or tricyclic, and further in one embodiment, it is a 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or a fused cycloalkyl group optionally fused with a heterocyclic group, an aryl group or a heteroaryl group. Non-limiting examples of fused cycloalkyl groups include:

[0125] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the bridged cycloalkyl group comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of constituent rings, the bridged cycloalkyl group may be bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:

[0126] The term "cycloalkylene" refers to a divalent cycloalkyl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the cycloalkyl group is as defined above.

[0127] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted by oxygen, but does not include the ring part of -OO-, -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group comprises 3 to 20, 3 to 14, 5 to 14, 7 to 14, 3 to 12, 5 to 12, 7 to 12, 7 to 10, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) or 7 to 12 (e.g., 7, 8, 9, 10, 11, 12) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0128] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl according to the number of spirohetero atoms shared between the rings; monospiroheterocyclyl and bispiroheterocyclyl are preferred; in one embodiment, the spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

[0129] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclyl is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is an optionally substituted or fused heterocyclyl described elsewhere herein, or a cycloalkyl, heterocyclyl, aryl or heteroaryl group; non-limiting examples of fused heterocyclyls include:

[0130] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In specific embodiments, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups; preferably bicyclic, tricyclic or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0131] The term "tricyclic heterocyclic group" refers to a heterocyclic group having three rings in the system, wherein the three rings may be a paracyclic system, a spirocyclic system or a bridged ring system. In one embodiment, the tricyclic heterocyclic group is a system in which at least one of the three rings is a heterocyclic group, and the other two rings may be cycloalkyl, heterocyclic, aryl or heteroaryl. The definitions of cycloalkyl, heterocyclic, aryl or heteroaryl are as described above. Non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:

[0132] wait.

[0133] The term "heterocyclylene" refers to a divalent heterocyclic group in which one hydrogen atom of a heterocyclic group is further substituted, wherein the heterocyclic group is optionally substituted or unsubstituted, and the heterocyclic group is as defined above.

[0134] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted with one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, 6 to 12, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is aromatic and the other rings may be saturated, partially unsaturated, or contain one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl group, a benzo 3-10 membered cycloalkyl group, or a benzo 3-10 membered heterocyclyl group. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl group, a benzo 3-6 membered cycloalkyl group, or a benzo 3-6 membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0135] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0136] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 5 to 20, 5 to 14, 5 to 12 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in particular embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0137] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0138] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0139] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0140] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0141] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0142] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0143] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0144] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

[0145] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0146] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0147] The term "aminocarbonyl" refers to NH2-C(O)-.

[0148] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0149] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0150] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0151] The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "oxo" or "oxo" refers to =0.

[0152] The term "C(X)" or "C(=X)" refers to When X is O, it represents that the group is a carbonyl group; when X is S, it represents that the group is a thiol group; when X is NR, it represents that the group is When X is CRR, it represents the group

[0153] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0154] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituents are selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0155] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0156] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0157] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0158] "Substituted" refers to any one or more hydrogen atoms on a particular atom being replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment in one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" refers to being substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. The substituent can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

[0159] "Substituted or unsubstituted" means that it may be substituted or unsubstituted. When it may be substituted, the substituent is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -SF5, -C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, C(O)R, C(O)OR, C(O)NRR', N=S(O)RR', S(O)R(=NR'), P(O)RR' or =RR';

[0160] R and R' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, --C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12aryl or 5-12 membered heteroaryl.

[0161] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0162] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0163] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0164] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0165] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0166] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0167] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0168] "Optically active" and "enantiomeric active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

[0169] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of the optical rotations (+) and (-) have nothing to do with the absolute configuration, R or S, of the molecule. DETAILED DESCRIPTION

[0170] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0171] Example

[0172] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0173] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0174] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0175] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0176] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0177] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0178] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0179] Unless otherwise specified in the examples, reactions can be carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of approximately 1 L. Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of approximately 1 L.

[0180] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0181] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0182] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0183] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0184] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0185] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0186] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0187] The chiral preparative HPLC conditions in the examples are as follows: R Indicates retention time:

[0188] Chiral preparation conditions:

[0189] Chiral analysis conditions:

[0190] The compounds in the embodiments of the present invention are prepared by referring to the following example preparation steps:

[0191] Example 1

[0192] 4-Amino-1-methyl-10-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7,8,9,10-tetrahydroazepino[3,4-g]pyrazolo[4,3-c]quinolin-11(1H)-one

[0193] Step 1: Disperse methyl 4-amino-2-bromo-formate 1a (10.00 g, 43.67 mmol) and N-iodosuccinimide (10.13 g, 45.00 mmol) in 100 mL of acetonitrile. Stir and react at 25°C for 16 hours. Filter the reaction mixture to remove insoluble matter. The filtrate is concentrated to dryness under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System A to yield 1b (14.00 g) in a 90.3% yield. MS m / z (ESI): 356 [M+1] +

[0194] Step 2: Disperse 1b (9.00 g, 25.35 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol (10.55 g, 50.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.86 g, 2.54 mmol), and potassium phosphate (10.75 g, 50.70 mmol) in 1,4-dioxane (150 mL) and water (30 mL). Stir and react at 80°C for 16 hours. The reaction mixture was filtered to remove insoluble matter. The filtrate was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 1c (6.50 g) in an 83.0% yield. MS m / z (ESI): 310 [M+1]. +

[0195] Step 3: Disperse 1c (6.50 g, 21.04 mmol) and potassium N,N'-carbonyldiimidazole phosphate (6.82 g, 42.08 mmol) in 65 mL of N-methylpyrrolidone. Stir and react at 150°C for 1 hour. Pour the reaction solution into 650 mL of water. A solid precipitates and is filtered to obtain 1d (5.71 g). Yield: 81.0%. MS m / z (ESI): 336 [M+1] +

[0196] Step 4: Disperse 1d (5.71 g, 17.04 mmol), 2,4-dimethoxybenzylamine (5.69 g, 34.08 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.18 g, 34.08 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (15.06 g, 34.08 mmol) in 50 mL of dimethyl sulfoxide. Stir and react at 25°C for 1 hour. The reaction solution was poured into 500 mL of water. A solid precipitated and was filtered to obtain 1e (6.41 g) in a 77.7% yield. MS m / z (ESI): 486 [M+1]. +

[0197] Step 5: 1e (5.2 g, 10.72 mmol), 4,4,5,5-tetramethyl-2-(3-(tetrahydro-2H-pyran-2-yl)oxypropyl)-1,3,2-dioxaborolane (4.3 g, 13.19 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (800 mg, 1.10 mmol), and cesium carbonate (5.37 g, 16.48 mmol) were dissolved in 60 mL of dioxane and 15 mL of water. The reaction was microwaved at 110 °C under nitrogen for 2 h. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to obtain 1f (3.3 g) in a 51.7% yield. MS m / z (ESI): 549 [M+1] +

[0198] Step 6: Dissolve 1f (3.3 g, 6.01 mmol) in 60 mL of methanol, add 12 mL of trifluoroacetic acid, and stir the reaction at room temperature for 2 hours. The reaction mixture was adjusted to pH 8-9 with aqueous sodium bicarbonate solution and extracted with dichloromethane (10% methanol, 100 mL x 2). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System C to yield 1g (2.2 g) in a 78.9% yield. MS m / z (ESI): 465 [M+1] +

[0199] Step 7: Dissolve 1g (2.2g, 4.74mmol) in dichloromethane (120mL), purge the mixture with nitrogen three times, and cool to 0°C. Add triphenylphosphine (2.49g, 9.48mmol) and carbon tetrabromide (3.14g, 9.48mmol). Incubate the mixture at 25°C for 2 hours. The reaction mixture is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System C to yield 1h (1.92g) in a 77.1% yield. MS m / z (ESI): 527[M+1]. +

[0200] Step 8: 1h (543 mg, 1.03 mmol), 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (270 mg, 1.24 mmol), sodium iodide (309 mg, 2.06 mmol), and potassium carbonate (427 mg, 3.09 mmol) were dissolved in acetonitrile (60 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 80°C for 15 hours. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL × 2), and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System C to afford 1i (351 mg) in a 51.3% yield. MS m / z (ESI): 665 [M+1]. +

[0201] Step 9: 1i (351 mg, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL). Lithium hydroxide (63 mg, 2.64 mmol) was added, and the nitrogen atmosphere was purged three times. The reaction system was incubated at 25°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (50 mL × 3) and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 1j (237 mg) in a yield of 68.7%. MS m / z (ESI): 651 [M+1] +

[0202] Step 10: Dissolve 1j (234 mg, 0.36 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68 mg, 0.54 mmol) in N,N-dimethylformamide (20 mL). Add N,N-diisopropylethylamine (93 mg, 0.72 mmol, 72 μL). The reaction system is incubated at 25°C for 48 hours. Quench with water, extract with ethyl acetate (80 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent System A to afford 1k (122 mg) in a 53.9% yield. MS m / z (ESI): 633 [M+1]. +

[0203] Step 11: 1k (122 mg, 0.19 mmol) was dissolved in trifluoroacetic acid (2 mL) and the reaction was incubated at 90°C for 0.5 h. The residue was concentrated and purified by silica gel column chromatography using eluent System A to afford Example 1 (47 mg) in a 50.5% yield. MS m / z (ESI): 483 [M+1] +

[0204] 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.33(dd,1H),8.22(s,1H),8.08(br s,2H),7.87(dd,1H),7.44(d,1H),6.71(t,1H),5.63-5.36(m,1H),4.89-4.70( m,2H),4.47-4.13(m,2H),3.94-3.64(m,2H),3.09(dd,2H),2.18-1.91(m,2H).

[0205] Example 1-P1 & 1-P2

[0206] Example 1 (45 mg, 0.093 mmol) was separated by chiral preparative HPLC to give rel-(S)-4-amino-1-methyl-10-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7,8,9,10-tetrahydroazepino[3,4-g]pyrazolo[4,3-c]quinolin-11(1H)-one 1- P1 (21 mg), yield: 46.7% and rel-(R)-4-amino-1-methyl-10-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7,8,9,10-tetrahydroazepino[3,4-g]pyrazolo[4,3-c]quinolin-11(1H)-one 1-P2 (21 mg), yield: 46.7%.

[0207] 1-P1: 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.33(dd,1H),8.22(s,1H),8.08(br s,2H),7.87(dd,1H),7.44(d,1H),6.71(t,1H),5.63-5.36(m,1H),4.89-4.70( m,2H),4.47-4.13(m,2H),3.94-3.64(m,2H),3.09(dd,2H),2.18-1.91(m,2H).

[0208] 1-P2: 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.33(dd,1H),8.22(s,1H),8.08(br s,2H),7.87(dd,1H),7.44(d,1H),6.71(t,1H),5.63-5.36(m,1H),4.89-4.70( m,2H),4.47-4.13(m,2H),3.94-3.64(m,2H),3.09(dd,2H),2.18-1.91(m,2H).

[0209] The preparation of the following examples is with reference to Example 1:

[0210] Alternatively, the synthesis of Examples 14, 15, and 48 may be performed by referring to the following preparation method:

[0211] Example 14

[0212] 4-Amino-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolidinone[8,7-g]quinoxalin-13(7H)-one

[0213] Step 1: 3-((tert-Butyldimethylsilyl)oxy)propan-1-ol 14a (10 g, 52.53 mmol) was dissolved in 100 mL of tetrahydrofuran. Sodium hydride (2.73 g, 68.29 mmol, 60% purity) was added under ice-cooling. After stirring for 15 minutes, potassium (bromomethyl)trifluoroborate (10.02 g, 49.91 mmol) was added and the reaction was stirred at room temperature for approximately 16 hours. Potassium bifluoride solution (4.5 M) was added to the reaction solution and stirred at room temperature for 30 minutes. The reaction solution was spin-dried and then added to 1000 L of hot acetone. The solution was stirred at 80°C for approximately 15 minutes. After hot filtration to remove impurities, the acetone was distilled under reduced pressure until solids precipitated. Two times the amount of ether was added, and the solution was filtered under ice-cooling. The residue was dried to afford 14b (4.3 g) in a 26.4% yield.

[0214] Step 2: Methyl 7-bromo-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (5.2 g, 10.99 mmol), potassium 8,8,9,9-tetramethyl-3,7-dioxa-8-sila-1-boradecane-1-trifluoroborate 14b (4.3 g, 13.19 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (800 mg, 1.10 mmol), and cesium carbonate (5.37 g, 16.48 mmol) were dissolved in 60 mL of dioxane and 15 mL of water. The reaction was microwaved at 110 °C under nitrogen atmosphere for 2 h. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford compound 14c (3.3 g) in a 50.5% yield. MS m / z (ESI): 595 [M+1]. +

[0215] Step 3: Dissolve 14c (3.3 g, 5.56 mmol) in 60 mL of tetrahydrofuran and add tetrabutylammonium fluoride (2.90 g, 11.10 mmol, 2 M in THF). Stir the reaction at room temperature for 2 hours. Quench the reaction mixture with saturated ammonium chloride solution (100 mL) and extract with ethyl acetate (100 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System C to afford 14d (1.5 g) in a 56.3% yield. MS m / z (ESI): 481 [M+1]. +

[0216] Step 4: Dissolve 14d (1.5 g, 3.12 mmol) in dichloromethane (120 mL), purge the atmosphere with nitrogen three times, and cool to 0°C. Triphenylphosphine (1.64 g, 6.24 mmol) and carbon tetrabromide (2.07 g, 6.24 mmol) are then added, and the reaction is continued at 25°C for 2 hours. The reaction solution is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System C to afford 14e (630 mg) in a 37.1% yield. MS m / z (ESI): 543 [M+1] +

[0217] Step 5: 14e (560 mg, 1.03 mmol), 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (270 mg, 1.24 mmol), sodium iodide (309 mg, 2.06 mmol), and potassium carbonate (427 mg, 3.09 mmol) were dissolved in acetonitrile (60 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 80°C for 15 hours. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL × 2), and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System C to afford 14f (360 mg) in a 51.3% yield. MS m / z (ESI): 681 [M+1]. +

[0218] Step 6: 14f (350 mg, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL). Lithium hydroxide (62 mg, 2.57 mmol) was added, and the nitrogen atmosphere was purged three times. The reaction system was incubated at 25°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (50 mL × 3) and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 14 g (125 mg), with a yield of 36.5%. MS m / z (ESI): 667 [M+1].+

[0219] Step 7: Dissolve 14 g (125 mg, 0.18 μmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68 mg, 0.54 mmol) in N,N-dimethylformamide (20 mL). Add N,N-diisopropylethylamine (93 mg, 0.72 mmol, 72 μL). The reaction system is incubated at 25°C for 48 hours. Quench with water, extract with ethyl acetate (80 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent System A to afford 14h (63 mg) in a 53.9% yield. MS m / z (ESI): 649 [M+1]. +

[0220] Step 8: 14h (63 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (2 mL) and the reaction was incubated at 90°C for 0.5 h. The residue was concentrated and purified by silica gel column chromatography using eluent System A to afford Example 14 (9.7 mg) in a 19.4% yield. MS m / z (ESI): 499 [M+1] +

[0221] 1 H NMR(400MHz,DMSO-d6)δ9.23(d,1H),8.33(dd,1H),8.22(s,1H),8.08(s,2H),7.87(dd,1H),7.44(d,1H),5.63–5. 36(m,1H),4.89–4.70(m,3H),4.47–4.13(m,3H),3.94–3.64(m,2H),3.09(dd,2H),2.18–1.91(m,1H),1.15(d,1H).

[0222] Example 15

[0223] 4-Amino-9-methyl-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one

[0224] Step 1: Dissolve 4-aminobutan-2-ol 15a (1.5 g, 16.83 mmol) and isobenzofuran-1,3-dione (2.99 g, 20.19 mmol) in toluene (15 mL). The atmosphere was replaced with nitrogen three times and then protected with nitrogen. The reaction was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to afford 15b (2.5 g) in a 67.8% yield. MS m / z (ESI): 220 [M+1] +

[0225] Step 2: NaH (729.81 mg, 18.25 mmol, 60% purity) was suspended in DMF (10 mL). The reaction system was cooled to 0°C, and 15b (2 g, 9.12 mmol) in DMF (10 mL) was added. The mixture was stirred at 0°C for 15 min, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.89 g, 18.25 mmol) in DMF (10 mL) was added. The atmosphere was replaced with nitrogen three times under nitrogen protection. The reaction was stirred at 25°C for 6 h. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with water (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated and purified by Pre-HPLC to obtain 15c (2 g) in a yield of 79.1%. MS m / z(ESI):278[M+1] +

[0226] Step 3: 7-Bromo-4-[(2,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (1.5 g, 3.18 mmol) and [3-(1,3-dioxoindole-2-yl)-1-methylpropoxy]methylboronic acid 15c (1.06 g, 3.82 mmol) were dissolved in 1'4-Dioxane (15 mL) and water (1.5 mL), and cataCXium APd was added sequentially. G3 (347.68 mg, 477 μmol) and Cs2CO3 (3.11 g, 9.55 mmol) were replaced with nitrogen three times under a nitrogen atmosphere. The reaction was stirred at 110°C in a microwave oven for 1.5 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with water (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified using Purification System C to afford compound 15d (3 g) in a 25.2% yield. MS m / z (ESI): 624 [M+1]. +

[0227] Step 4: 15d (3 g, 2.41 mmol) was dissolved in EtOH (30 mL), and NH2NH2 (181.35 mg, 4.81 mmol, 85% purity) was added. The atmosphere was replaced with nitrogen three times, and a nitrogen atmosphere was applied. The reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to afford 15e (470 mg) in a 39.6% yield. MS m / z (ESI): 494 [M+1] +

[0228] Step 5: [2-(Trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]methanesulfonate (100 mg, 336 μmol) and 15e (182.64 mg, 370 μmol) were dissolved in MeCN (10 mL). NaI (100.85 mg, 673 μmol) and DIEA (86.96 mg, 673 μmol, 117 μL) were added sequentially. The atmosphere was purged with nitrogen three times under a nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 15f (155 mg) in a 66.3% yield. MS m / z (ESI): 695 [M+1]. +

[0229] Step 6: 15f (155 mg, 223 μmol) was dissolved in THF (3 mL), MeOH (1 mL), and water (1 mL). LiOH (21.37 mg, 892.47 μmol) was added and the atmosphere was replaced with nitrogen three times under a nitrogen atmosphere. The reaction was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, dissolved in water (10 mL), and the pH was adjusted to 4-5 with 2M dilute hydrochloric acid. The solution was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 15 g (52 mg). Yield: 34.2%. MS m / z (ESI): 682 [M+1]. +

[0230] Step 7: Dissolve 15g (52mg, 76μmol) in DMF (5mL), add DIEA (29.62mg, 229μmol, 39.92μL) and HATU (43.23mg, 115μmol) in sequence, replace the nitrogen atmosphere three times, and turn on nitrogen protection. The reaction is stirred at 25°C for 16 hours; the reaction solution is concentrated under reduced pressure to obtain 15h (50mg, crude).

[0231] Step 8: 15h (50 mg, 60 μmol) was dissolved in TFA (2 mL), and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 80°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by Pre-HPLC to obtain Example 15 (17 mg). MS m / z (ESI): 513 [M+1] +

[0232] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.27(d,1H),7.99(s,1H),7.90(s,1H),7.85(d,1H),7.37(d,3H),5.38(s,1H ),4.92–4.71(m,3H),4.50–4.35(m,2H),4.26(dd,1H),3.67(d,1H),3.44(dd,1H),1.32–1.03(m,3H),0.94(d,3H).

[0233] Example 15-P1 & 15-P2

[0234] Example 15 (17 mg, 0.33 mmol) was separated by preparative HPLC to give an enantiomeric mixture of (R)-4-amino-9-methyl-12-((S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one and (S)-4-amino-9-methyl-12-((R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one 15-P1. (7.6 mg), yield: 44.7% and (R)-4-amino-9-methyl-12-((R)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one with (S)-4 -enantiomeric mixture of amino-9-methyl-12-((S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one 15-P2 (7.9 mg), yield: 46.5%.

[0235] 15-P1: 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.27(d,1H),7.99(s,1H),7.90(s,1H),7.85(d,1H),7.37(d,3H),5.38(s,1H ),4.92–4.71(m,3H),4.50–4.35(m,2H),4.26(dd,1H),3.67(d,1H),3.44(dd,1H),1.32–1.03(m,3H),0.94(d,3H).

[0236] 15-P2: 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.27(d,1H),7.99(s,1H),7.90(s,1H),7.85(d,1H),7.37(d,3H),5.38(s,1H ),4.92–4.71(m,3H),4.50–4.35(m,2H),4.26(dd,1H),3.67(d,1H),3.44(dd,1H),1.32–1.03(m,3H),0.94(d,3H).

[0237] Example 48

[0238] 4-Amino-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydro-7H-imidazo[1,5-a][1,6]oxazino[3,4-g]quinoxalin-14(9H)-one

[0239] Step 1: Dissolve 4-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol 48a (6.6 g, 37.88 mmol) in 100 mL of tetrahydrofuran. Add sodium hydride (1.52 g, 37.88 mmol, 60% purity) in an ice bath. Stir for 15 minutes, then add potassium (bromomethyl)trifluoroborate (7.61 g, 37.88 mmol). Stir the mixture at room temperature for approximately 16 hours. Add potassium bifluoride solution (4.5 M) to the reaction mixture, stir at room temperature for 30 minutes, spin dry, add 100 mL of hot acetone, and stir at 80°C for approximately 15 minutes. After hot filtration to remove impurities, distill the acetone under reduced pressure until solids precipitate. Add twice the amount of ether, filter the mixture in an ice bath, and dry the residue to obtain 48b (6.7 g, 22.78 mmol) in a 60.1% yield.

[0240] Step 2: Compound 48b (1.25 g, 4.24 mmol) was dissolved with [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (309.05 mg, 424.36 μmol) and cesium carbonate (4.15 g, 12.73 mmol) in 40 mL of dioxane and 10 mL of water. The reaction mixture was allowed to react at 100°C under nitrogen for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford compound 48c (2.46 g) in 100% yield. MS m / z (ESI): 579 [M+1]. +

[0241] Step 3: 48c (2.46 g, 4.25 mmol) was added to a single-necked flask containing methanol (20 mL) and tetrahydrofuran (20 mL). p-Toluenesulfonic acid (73.12 mg, 425.12 μmol) was added under nitrogen and stirred at room temperature for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System C to afford 48d (1.9 g) in a 90.4% yield. MS m / z (ESI): 495 [M+1]. +

[0242] Step 4: Dissolve 48d (2 g, 4.04 mmol) in dichloromethane (20 mL), purge the mixture with nitrogen three times, and cool to 0°C. Triphenylphosphine (1.59 g, 6.07 mmol) and carbon tetrabromide (2.01 g, 6.07 mmol) are then added, and the reaction is continued at 25°C for 2 hours. The reaction mixture is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System C to afford 48e (1.5 g) in a 66.5% yield. MS m / z (ESI): 558 [M+1] +

[0243] Step 5: 48e (0.5 g, 896.97 μmol), 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (391.39 mg, 1.79 mmol), sodium iodide (269.09 mg, 1.79 mmol), and DIEA (352.50 mg, 2.73 mmol, 475.07 μL) were dissolved in acetonitrile (20 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 80°C for 15 hours. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL × 2), and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System C to afford 48f (190 mg) in a 30.5% yield. MS m / z (ESI): 695 [M+1]. +

[0244] Step 6: Dissolve 48f (0.19 g, 273.50 μmol) in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL). Add lithium hydroxide (45.95 mg, 1.09 mmol). The nitrogen atmosphere is purged three times, and the reaction system is incubated at 25°C for 16 hours. Adjust the pH to 5-6 with 1M dilute hydrochloric acid. Extract with ethyl acetate (50 mL × 3) and wash with saturated brine (50 mL × 2). The organic phase is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to yield 48 g (130 mg), with a yield of 69.8%. MS m / z (ESI): 681 [M+1]. +

[0245] Step 7: Dissolve 48 g (65 mg, 95.49 μmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54.43 mg, 143.24 μmol) in N,N-dimethylformamide (5 mL). Add N,N-diisopropylethylamine (37.03 mg, 286.48 μmol, 49.90 μL). The reaction system is incubated at 25°C for 48 hours. Quench with water, extract with ethyl acetate (80 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent System A to afford 48h (63.28 mg, 95.49 μmol) in 100% yield. The crude product is directly used in the next step. MS m / z (ESI): 663 [M+1] +

[0246] Step 8: 48h (63.28 mg, 95.49 μmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction was incubated at 90°C for 0.5 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography using eluent System A to afford Example 48 (12 mg) in a 24.5% yield. MS m / z (ESI): 513 [M+1] +

[0247] 1 H NMR(400MHz,DMSO-d6)δ9.32(d,1H),8.94(s,1H),8.37–8.11(m,3H),7.89(t,1H),7.48(d,1 H),5.70(s,1H),5.01–4.71(m,3H),4.55–4.11(m,3H),3.84–3.56(m,4H),2.05–1.28(m,4H).

[0248] Example 62

[0249] (Z)-4-((2,4-dimethoxybenzyl)amino)-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazepine[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one

[0250] Step 1: Dissolve 2-(trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 62a (3 g, 13.82 mmol) and hydroxylamine hydrochloride (960 mg, 13.82 mmol) in ethanol (30 mL) and sodium acetate (3.40 g, 41.45 mmol). The nitrogen atmosphere was purged three times and the system was reacted at 80°C for 1 hour. Cool to room temperature, concentrate, quench with water, extract with ethyl acetate (100 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel column chromatography with eluent System B to afford 62b (3.10 g) in a 96.7% yield. MS m / z (ESI): 233 [M+1] +

[0251] Step 2: Dissolve 62b (3.1 g, 13.35 mmol) and wet palladium on carbon (811 mg, 0.67 mmol, 10% purity) in methanol (40 mL). The hydrogen atmosphere was evacuated three times and the reaction was carried out under a hydrogen balloon at 25°C for 4 hours. Filtration and concentration afforded 62c (2.80 g, crude product). MS m / z (ESI): 219 [M+1] +

[0252] Step 3: Methyl 7-bromo-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 62d (1 g, 2.12 mmol) and cuprous iodide (81 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (11 mL) and triethylamine (11 mL). The atmosphere was purged with nitrogen three times. Hex-5-yn-1-ol (1.04 g, 10.61 mmol) and bistriphenylphosphine palladium dichloride (149 mg, 0.21 mmol) were added. The atmosphere was purged with nitrogen three times. The system was reacted at 40°C for 16 hours. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (60 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 62e (0.95 g, crude product). MS m / z (ESI): 489 [M+1] +

[0253] Step 4: Dissolve 62e (0.95 g, 1.94 mmol) and Raney nickel (100 mg) in methanol (10 mL) and tetrahydrofuran. The hydrogen atmosphere was evacuated three times and the reaction was carried out under a hydrogen balloon at 25°C for 0.5 h. Filter and concentrate to afford 62f (0.90 g, crude product). MS m / z (ESI): 491 [M+1] +

[0254] Step 5: Dissolve 62f (0.9 g, 1.83 mmol) in dichloromethane (10 mL), purge with nitrogen three times, and cool to 0°C. Triphenylphosphine (962 mg, 3.67 mmol) and carbon tetrabromide (1.22 g, 3.67 mmol) are then added. The reaction mixture is allowed to react at 25°C for 2 hours. The mixture is concentrated. The residue is purified by silica gel column chromatography using eluent System B to afford 62f (560 mg) in a 55.2% yield. MS m / z (ESI): 553 [M+1] +

[0255] Step 6: Dissolve 62g (1g, 1.81mmol), 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (788mg, 3.61mmol), and sodium iodide (541.67mg, 3.61mmol) in acetonitrile (60mL). Add N,N-diisopropylethylamine (1.40g, 10.84mmol, 1.89mL), purge with nitrogen three times, and react at 80°C for 15 hours. Quench with water, extract with ethyl acetate (80mL×3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is purified by silica gel column chromatography with eluent system A to obtain 62h (410mg) in a yield of 32.9%. MS m / z (ESI): 691[M+1] +

[0256] Step 7: Dissolve 62h (430 mg, 0.62 mmol) in tetrahydrofuran (5 mL), water (5 mL) and methanol (5 mL), add lithium hydroxide (60 mg, 2.49 mmol), evacuate nitrogen three times, and react at 25°C for 16 hours. Add 1M dilute hydrochloric acid to adjust the pH to 5-6, extract with ethyl acetate (50 mL × 3), wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate to give 62i (410 mg, crude product). MS m / z (ESI): 677 [M+1] +

[0257] Step 8: Dissolve 62i (56 mg, 83 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (62 mg, 0.17 mmol) in N,N-dimethylformamide (10 mL). Add N,N-diisopropylethylamine (54 mg, 0.41 mmol, 72 μL). The atmosphere was purged with nitrogen three times. The reaction system was incubated at 25°C for 48 hours. The mixture was quenched with water and extracted with ethyl acetate (80 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 62j (16 mg) in a 29.4% yield. MS m / z (ESI): 659 [M+1]. +

[0258] Step 9: Dissolve 62j (5 mg, 7.6 μmol) in trifluoroacetic acid (2 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 90°C for 0.5 h. After concentration, the residue was purified by silica gel column chromatography using eluent System A to afford Example 62 (0.55 mg) in a 14.2% yield. MS m / z (ESI): 509 [M+1]. +

[0259] 1 H NMR(400MHz,MeOD)δ9.07(d,1H),8.27(d,1H),8.18–8.06(m,1H),7.99–7.92(m ,1H),7.79(dd,3.0Hz,1H),7.25(d,1H),6.65(dd,1H),6.10–5.99(m,1H),5.88 –5.78(m,1H),4.51(dd,1H),4.34(dd,1H),4.28–4.20(m,1H),3.65–3.58(m,1H ),3.09–2.98(m,1H),2.13(s,1H),2.04–1.96(m,1H),1.56(s,3H),1.29(s,2H).

[0260] Example 62-P1 & 62-P2

[0261] Example 62 (55 mg, 4.24 mmol) was separated by chiral preparative HPLC to obtain rel-(R,Z)-4-amino-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazadecano[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one 62 -P1 (18 mg), yield: 32.7% and rel-(S,Z)-4-amino-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazepine[4,3-g]imidazo[1,5-a]quinoxaline-14(9H)-one 62-P2 (20 mg), yield: 36.4%.

[0262] 62-P1(t R :1.624min): 1 H NMR(400MHz,MeOD)δ9.06(dd,1H),8.21(dd,1H),8.08–7.91(m,2H),7.78(d d,1H),7.25(dd,1H),6.65(dd,1H),6.09–5.77(m,1H),5.52–5.26(m,1H),4. 60(s,1H),4.51(dd,1H),4.23(ddd,1H),3.62(t,1H),3.04(dt,1H),2.23–2. 07(m,1H),2.03–1.95(m,1H),1.77(q,1H),1.60(dt,1H),1.45–1.20(m,3H).

[0263] 62-P2(t R :1.410min): 1 H NMR(400MHz,MeOD)δ8.97(d,1H),8.12(dd,1H),7.98–7.82(m,2H),7.69(dd,1H),7.15(d,1H),6.55(dd,1H),6.00–5.69(m,1H),5.42–5.16(m,1H),4 .42(dd,1H),4.28–4.08(m,2H),3.52(t,1H),2.95(dt,1H),2.12–1.97(m, 1H),1.93–1.84(m,1H),1.71–1.61(m,1H),1.46(d,1H),1.37–1.05(m,3H).

[0264] Example 63

[0265] 4-Amino-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-8,9,10,11,12,13-hexahydroazadecano[4,3-g]imidazo[1,5-a]quinoxalin-14(7H)-one

[0266] Step 1: (Z)-4-((2,4-dimethoxybenzyl)amino)-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazepine[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one 63a (15 mg, 23 μmol) and platinum dioxide (3 mg, 12 μmol) were dissolved in methanol (3 mL). The hydrogen atmosphere was evacuated three times and the reaction system was reacted under a hydrogen balloon at 25°C for 1 hour. The mixture was filtered and concentrated to afford 63b (12 mg, crude product).

[0267] Referring to the eighth step of Example 14, Example 63 (3 mg) was obtained from 63b (12 mg, 18 μmol) in a yield of 32.4%. MS m / z (ESI): 511 [M+1] +

[0268] The preparation of the following examples refers to Example 62:

[0269] Or the preparation of Examples 65, 77, and 157 adopts the following method:

[0270] Example 65

[0271] 4-Amino-11-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11-dihydro-7H-imidazo[1,5-a][1,4]oxazino[7,6-g]quinoxalin-12(9H)-one

[0272] Step 1: A solution of methyl 7-bromo-4-[(3,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinoxaline-8-carboxylate 65a (600 mg, 1.27 mmol), potassium trifluoro(2-tetrahydropyran-2-yloxyethoxymethyl)borate (677 mg, 2.55 mmol), cesium carbonate (827 mg, 2.55 mmol), and Cataxium A-Pd-G3 (93 mg, 0.13 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was sealed in a microwave tube under nitrogen purge and stirred at 110°C for 2.5 hours. The reaction mixture was filtered to remove solids, and the filtrate was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to afford 65c (210 mg) as a pale yellow oil in a 35.6% yield. MS m / z(ESI):467[M+1] +

[0273] Referring to the synthesis method of Example 62, Example 65 (22 mg) was obtained from 65c (620 mg, 1.33 mmol) in a yield of 3.7%. MS m / z (ESI): 485 [M+1] +

[0274] 1 H NMR(400MHz,MeOD)δ9.28(d,1H),8.40(m,2H),8.07,7.78(d,1H),7.75(m,1H),7.44(m,1H),6.03,5.83(s,1 H),5.00(m,2H),4.78(m,2H),4.42(m,1H),4.18(m,2H),3.95(m,1H),3.70(d,1H),3.42(m,1H),3.14(m,1H).

[0275] Example 77

[0276] 4-Amino-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5a,7,8,9,10,11,12,14a-octahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0277] Referring to the synthesis method from step 1 to step 2 of Example 63, (Z)-4-((3,5-dimethoxybenzyl)amino)-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one 77a (60 mg, 4.24 mmol) was used to obtain Example 77 (6 mg) in a 13.3% yield. MS m / z (ESI): 455 [M+1]. +

[0278] Example 157

[0279] (Z)-4-amino-11-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11-dihydroazocino[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one

[0280] Referring to steps 3 to 9 of Example 62, 7-bromo-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 62d (2 g, 4.25 mmol) was used to obtain Example 157 (22 mg) in a 1.1% yield. MS m / z (ESI): 481 [M+1]. +

[0281] 1 H NMR(400MHz,DMSO-d6)δ9.18(d,1H),8.22(s,1H),8.15–8.05(m,1H),8.01–7.89(m,1H),7.84(dd,1H),7.62(s,2H),7.18(d,1 H),6.59(ddd,1H),5.93(m,1H),5.55(d,1H),4.94–4.74(m,2H),4.34–4.12(m,2H),3.76(dd,2H),3.16(d,1H),2.76(td,1H).

[0282] Example 158

[0283] (Z)-4-amino-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0284] Referring to the synthesis method of steps 3 to 9 of Example 62, Example 158 (23 mg) was obtained from methyl 7-bromo-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 158a (2 g, 4.24 mmol) in a 1.1% yield. MS m / z (ESI): 495 [M+1]. +

[0285] 1 H NMR(400MHz,MeOD)δ9.05(s,1H),8.19–8.08(m,2H),7.95(s,1H),7.78(dd,1H),7.31(d,1H),6.63(dd,,1H),6.28–5.93(m ,1H),5.53(d,1H),4.43(dd,1H),4.34–4.16(m,2H),3.97–3.69(m,1H),3.42(d,1H),2.26–1.87(m,3H),1.54–1.26(m,2H).

[0286] Example 158-P1 & 158-P2

[0287] Example 158 (140 mg, 0.28 mmol) was separated by chiral preparative HPLC to give (R, Z)-4-amino-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydro-13H-aza[4,3-g]imidazo[1,5-a]quinoxaline-13-one 158- P1 (46 mg), yield 32.9% and rel-(R,Z)-4-amino-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydro-13H-aza[4,3-g]imidazo[1,5-a]quinoxalin-13-one 158-P2 (45 mg), yield 32.1%.

[0288] 158-P1(t R :1.733min): 1H NMR(400MHz,MeOD)δ9.05(s,1H),8.19–8.07(m,2H),7.93(s,1H),7.78(d,1H),7.30(s,1H),6.63(dd,1H),6.10(dq,1H),5.53(d,1H ),4.37(ddd,1H),4.22(ddd,1H),3.92(d,1H),3.72–3.60(m,1H),3.42(d,1H),2.21(dd,1H),2.12–1.88(m,2H),1.53–1.26(m,2H).

[0289] 158-P2(t R :0.771min): 1 H NMR(400MHz,MeOD)δ9.04(d,1H),8.20–8.08(m,2H),7.93(d,1H),7.78(d,1H),7.30(s,1H),6.63(dd,1H),6.31–5.90(m,1H),5.53 (d,1H),4.37(ddd,1H),4.22(ddd,1H),3.92(d,1H),3.66(t,1H),3.42(d,1H),2.21(dd,1H),2.13–1.86(m,2H),1.53–1.26(m,2H).

[0290] Example 159

[0291] 4-Amino-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7,8,9,10,11,12-hexahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0292] Referring to the synthesis method from step 1 to step 2 of Example 63, Example 159 (15 mg) was obtained from (Z)-4-((3,5-dimethoxybenzyl)amino)-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydro-13H-azepano[4,3-g]imidazo[1,5-a]quinoxalin-13-one 159a (110 mg, 4.24 mmol) in a 17.7% yield. MS m / z (ESI): 497 [M+1]. +

[0293] 1H NMR(400MHz,MeOD)δ9.06(d,1H),8.25–8.10(m,2H),7.96(d,1H),7.80(dd,1H),7.42(d,1H),6.05(s,1H),4.40–4.22(m,2H),3.94–3.84(m,1H) ,3.20(dd,1H),3.00(dd,1H),2.84–2.73(m,1H),2.58(ddd,1H),1.98(d ,2H),1.81–1.59(m,2H),1.50(s,1H),1.27–1.19(m,1H),1.07(dd,1H).

[0294] Alternatively, Examples 164, 165, and 167 may be prepared by the following method:

[0295] Example 164

[0296] (Z)-4-Amino-12-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0297] Step 1: Dissolve 6-(trifluoromethyl)benzofuran-3-one 164a (2 g, 9.89 mmol) in methanol (10 mL). The atmosphere was purged with nitrogen three times, and sodium borohydride (449 mg, 11.87 mmol) was added. The reaction was allowed to react at 25°C for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 164b (16 mg) in 89.1% yield. MS m / z (ESI): 205 [M+1]. +

[0298] Step 2: 164b (0.15 g, 0.73 mmol) was dissolved in tetrahydrofuran (5 mL), purged with nitrogen three times, and cooled to 0°C. Diphenylphosphinate (214 mg, 0.88 mmol, 168 μL) and 1,8-diazacyclo[5,4,0]undecene-7 (134 mg, 0.88 mmol, 132 μL) were added, and the reaction was stirred at 25°C for 16 hours. The reaction was quenched with water, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 164c (130 mg) in a 77.2% yield. MS m / z (ESI): 230 [M+1]. +

[0299] Step 3: 164c (0.13 g, 567.29 μmol) and triphenylphosphine (446 mg, 1.70 mmol) were dissolved in water (0.1 mL) and tetrahydrofuran (10 mL). The nitrogen atmosphere was purged three times and the reaction was incubated at 50°C for 15 hours. The reaction mixture was cooled to room temperature, and 0.5 M hydrochloric acid (30 mL) was added. The mixture was extracted three times with ethyl acetate (30 mL x 3). The aqueous phase was evaporated to dryness to afford 164d (60 mg) in a 52.2% yield.

[0300] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 164 (23 mg) was obtained from methyl (Z)-7-(5-bromopent-1-en-1-yl)-4-(2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 164e (500 mg, 0.93 mmol) in a 5.2% yield. MS m / z (ESI): 480 [M+1]. +

[0301] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),8.08(d,1H),7.86(s,1H),7.58–7.37(m,3H),7.24(t,1H),7.18–7.05(m,2H),6.45(dd ,1H),6.11–5.75(m,2H),4.84–4.72(m,1H),2.04(s,1H),1.92(s,1H),1.69(d,1H),1.37(d,1H),1.22(s,1H),1.08(s,1H).

[0302] Step 8: Example 164 (50 mg, 0.10 mmol) was separated by chiral preparative HPLC to obtain rel-(R,Z)-4-amino-12-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one 164-P1 (18 mg). Yield: 36.0%. MS m / z (ESI): 480 [M+1]. + and rel-(R,Z)-4-amino-12-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one 164-P2 (20 mg), yield: 40.0%, MS m / z (ESI): 480 [M+1] + .

[0303] 164-P1(t R :3.213min): 1 H NMR(400MHz,MeOD)δ9.01(s,1H),8.09(d,1H),7.93(d,1H),7.59(t,1H),7.33–7.25(m,2H),7.11(d,1H),6. 65–6.56(m,1H),6.18(d,1H),6.06–5.92(m,1H),4.81–4.71(m,2H),3.57(s,2H),2.17(s,2H),1.28(s,2H).

[0304] 164-P2(t R :3.006min): 1 H NMR(400MHz,MeOD)δ9.01(s,1H),8.09(d1H),7.93(d,1H),7.62–7.56(m,1H),7.32–7.24(m,2H),7.12(d,1 H),6.64–6.57(m,1H),6.19(s,1H),6.01(d,2H),4.81–4.72(m,2H),3.56(d,2H),2.17(s,2H),1.28(s,2H).

[0305] Example 165

[0306] (Z)-4-Amino-12-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3,9,10,11,12-hexahydro-13H-azo[3,4-g]furo[3,4-c]quinolin-13-one

[0307] Step 1: Dissolve methyl acetoacetate (82.88 g, 713.80 mmol) in glacial acetic acid (1 L). Add 4-ethoxy-1,1,1-trifluoro-3-buten-2-one 165a (100 g, 594.84 mmol) and ammonium acetate (183.40 g, 2.38 mol) sequentially. Stir at 120°C for 16 hours. Cool to room temperature, evaporate the acetic acid, quench with water, extract with ethyl acetate (2 L x 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is purified by silica gel column chromatography using eluent System A to afford 165b (80 g) in a 61.3% yield. MS m / z (ESI): 220 [M+1] +

[0308] Step 2: 165b (80.5 g, 367.31 mmol) was dissolved in carbon tetrachloride (800 mL). N-bromosuccinimide (130.75 g, 734.62 mmol) and azobisisobutyronitrile (12.06 g, 73.46 mmol) were added under nitrogen atmosphere and stirred at 77°C for 16 h. After the reaction, the solvent was dried to give crude product 165c (80 g), which was used directly in the next reaction. MS m / z (ESI): 376 [M+1] +

[0309] Step 3: Dissolve 165c (80 g, 365.03 mmol) in tetrahydrofuran (800 mL), add diethyl phosphite (30.25 g, 219.02 mmol) and N,N-diisopropylethylamine (28.31 g, 219.02 mmol, 38.15 mL), and react at 25°C for 2 hours. After the reaction, the mixture was dried and the residue was purified by silica gel column chromatography using eluent System A to afford 165d (80 g) in a 73.5% yield. MS m / z (ESI): 298 [M+1] +

[0310] Step 4: Sodium hydroxide (71.66 g, 1.79 mol) was added to a three-necked flask. Tetrahydrofuran (1.7 L) and methyl glycolate (64.55 g, 716.64 mmol) were added under an ice bath and nitrogen atmosphere. The mixture was stirred for half an hour. Then, 165d (178 g, 597.20 mmol) was added to the system. The reaction system was reacted at 25°C for 16 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate (2 L x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of 165e (187 g). MS m / z (ESI): 276 [M+1] +

[0311] Step 5: Dissolve 165e (187 g, 679.55 mmol) in a mixture of concentrated hydrochloric acid (500 mL) and 1,4-dioxane (500 mL). The reaction mixture was allowed to react at 110°C for 0.5 h. After the reaction, the solvent was evaporated, and the pH was adjusted to 8 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2 L x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A to afford 165f (37.9 g) in a yield of 25.6%. MS m / z (ESI): 218 [M+1]. +

[0312] Step 6: 2-(Trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 165f (21 g, 96.74 mmol) and hydroxylamine hydrochloride (6.72 g, 96.74 mmol) were dissolved in ethanol (210 mL) and sodium acetate (23.80 g, 290.15 mmol). The nitrogen atmosphere was purged three times and the system was reacted at 80°C for 1 hour. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (500 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent System B to give 165 g (21.70 g) in a yield of 96.7%. MS m / z (ESI): 233 [M+1] +

[0313] Step 7: Dissolve 165g (20.98g, 90.37mmol), zinc powder (59.08g, 903.69mmol), and ammonium chloride (48.34g, 903.69mmol) in ethanol (40mL) and react at 50°C for 4 hours. Filter, concentrate, and slurry with dichloromethane to obtain 165h (12.6g), yield: 63.9%. MS m / z (ESI): 219 [M+1] +

[0314] Step 8: Methyl 4-amino-5-bromo-2-chlorobenzoate 165i (80 g, 302.45 mmol), pinacol diboron (115.21 g, 453.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene (16.77 g, 30.25 mmol), potassium acetate (59.37 g, 604.91 mmol), and palladium acetate (3.40 g, 15.12 mmol) were added to 1,4-dioxane (800 mL). The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 165j (84 g, 269.60 mmol) in 89.1% yield. MS m / z (ESI): 312 [M+1]. +

[0315] Step 9: 165j (70.5 g, 226.27 mmol) was added to ethanol (1000 mL) and water (200 mL). Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (62.49 g, 226.27 mmol), sodium carbonate (47.97 g, 452.55 mmol), and bis(triphenylphosphine)palladium(II) chloride (15.88 g, 22.63 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction system was reacted at 80°C for 4 hours. The reaction solution was directly concentrated, stirred with water for 10 minutes, filtered, and the solid was slurried with ethyl acetate to obtain 165k (49 g, 175.20 mmol) in a yield of 77.4%. MS m / z (ESI): 280 [M+1] +

[0316] Step 10: 165k (56.7 g, 202.74 mmol) was dissolved in dimethyl sulfoxide (25.23 mL), and 2,4-dimethoxybenzylamine (40.68 g, 243.28 mmol) and 1,8-diazobisspiro[5.4.0]undec-7-ene (92.59 g, 608.21 mmol, 90.78 mL) were added. Finally, Carter condensation agent (269.00 g, 608.21 mmol) was added. The reaction system was allowed to react at room temperature for 1 hour. The reaction solution was added to ice water and extracted with ethyl acetate. The organic phase was dried, concentrated, and slurried with methanol to obtain 165l (43 g, 100.26 mmol) in a 49.5% yield. MS m / z (ESI): 429 [M+1]. +

[0317] Step 11: 165l (5 g, 11.66 mmol) was dissolved in N,N-dimethylformamide (50 mL) in a sealed tube. 2-(4-pentynyloxy)tetrahydro-2H-pyran (2.94 g, 17.49 mmol), cesium carbonate (7.60 g, 23.32 mmol), dichlorobis(tricyclohexylphosphine)palladium (860.62 mg, 1.17 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.11 g, 2.33 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction system was reacted at 100°C for 2 hours. The reaction solution was added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 165m (6.05 g, 10.79 mmol) in a 92.6% yield. MS m / z(ESI):561[M+1] +

[0318] Step 12: Dissolve 165m (6.05 g, 10.79 mmol) in methanol (60 mL) and add trifluoroacetic acid (12 mL). The reaction mixture is allowed to react at room temperature for 1 hour. The reaction mixture is adjusted to pH 8-9 by adding aqueous sodium bicarbonate solution, extracted with dichloromethane (10% methanol), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography using eluent System B to afford 165n (3.64 g, 7.64 mmol) in a yield of 70.8%. MS m / z (ESI): 477 [M+1] +

[0319] Step 13: 165n (1 g, 2.10 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL). Nickel acetate tetrahydrate (104.44 mg, 419.71 μmol) was added. Sodium borohydride (158.78 mg, 4.20 mmol) was slowly added portionwise at room temperature. The reaction system was allowed to react at room temperature for 3 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 165o (0.39 g, 0.81 mmol) in a yield of 38.8%. MS m / z (ESI): 479 [M+1] +

[0320] Step 14: Dissolve 165o (1.3 g, 2.72 mmol) in dichloromethane (30 mL). Add carbon tetrabromide (3.60 g, 10.87 mmol) and triphenylphosphine (2.85 g, 10.87 mmol). Stir the reaction at room temperature for 3 hours. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography using eluent System A to afford 165p (1.27 g, 2.35 mmol) in an 86.3% yield. MS m / z (ESI): 541 [M+1]. +

[0321] Step 15: 165p (1.4 g, 2.59 mmol) was dissolved in acetonitrile (30 mL). 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (676.97 mg, 3.10 mmol), potassium carbonate (1.07 g, 7.76 mmol), and sodium iodide (775.15 mg, 5.17 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction system was reacted at 80°C for 16 hours. The mixture was quenched with water, extracted with ethyl acetate (150 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 165q (726 mg, 1.07 mmol) in a 41.4% yield. MS m / z (ESI): 679 [M+1].+

[0322] Step 16: 165q (762 mg, 1.12 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide monohydrate (141.33 mg, 3.37 mmol) was added, and the reaction system was reacted at 50°C for 3 hours. The reaction solution was concentrated to remove the organic phase, adjusted to neutrality with 2N hydrochloric acid, extracted with dichloromethane (10% methanol), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 165r (553 mg, 831.99 μmol) in a yield of 74.1%. MS m / z (ESI): 665 [M+1] +

[0323] Step 17: 165r (553 mg, 831.99 μmol) was dissolved in N,N-dimethylformamide (20 mL). N,N-diisopropylethylamine (215.05 mg, 1.66 mmol, 289.83 μL) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (470.83 mg, 1.25 mmol) were added. The reaction system was stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with ethyl acetate (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 165s (436 mg, 674.24 μmol) in an 81.0% yield. MS m / z (ESI): 647 [M+1]. +

[0324] Step 18: 165s (436 mg, 674.24 μmol) was added to trifluoroacetic acid (10 mL), and the reaction system was reacted at 80°C for 1 hour. The reaction solution was adjusted to pH 8-9 with aqueous sodium bicarbonate solution, extracted with dichloromethane (10% methanol), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to provide Example 165 (121 mg) in a yield of 36.15%. MS m / z (ESI): 497 [M+1] +

[0325] Example 165-P1 & 165-P2

[0326] Example 165 (388 mg, 0.78 mmol) was separated by chiral preparative HPLC to give rel-(S)-(Z)-4-amino-12-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3,9,10,11,12-hexahydro-13H-azacyclononano[3,4-g]furo[3,4-c]quinolin-13-one 165 -P1 (181 mg, 46.6% yield) and rel-(R)-(Z)-4-amino-12-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3,9,10,11,12-hexahydro-13H-azacyclononano[3,4-g]furo[3,4-c]quinolin-13-one 165-P2 (177 mg, 45.6% yield).

[0327] 165-P1(t R :3.029min): 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,1H),7.86(dd,1H),7.46(d,2H),7.28(d,1H),6.66(s,1H),6.60(q,1H),6.50-5.70(m,1H),5.50-5. 10(m,1H),5.34(s,2H),5.03(s,2H),4.93-4.74(m,2H),4.34-4.13(m,2H),3.75-3.10(m,2H),2.18-1.70(m,2H),1.45-1.25(m,2H).

[0328] 165-P2(t R :2.383min): 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,1H),7.86(dd,1H),7.46(d,2H),7.28(d,1H),6.66(s,1H),6.60(q,1H),6.50-5.70(m,1H),5.50-5. 10(m,1H),5.34(s,2H),5.03(s,2H),4.93-4.74(m,2H),4.34-4.13(m,2H),3.75-3.10(m,2H),2.18-1.70(m,2H),1.45-1.25(m,2H).

[0329] Example 167

[0330] (Z)-4-Amino-12-(7-trifluoromethylisochroman-4-yl)-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0331] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 167 (7 mg) was obtained from 62 g (1.08 g, 2.00 mmol) of methyl (Z)-7-(6-bromopent-1-en-1-yl)-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate. The yield was 0.7%. MS m / z (ESI): 494 [M+1]. +

[0332] 1 H NMR(400MHz,DMSO-d6)δ9.12(d,1H),8.16(dd,1H),7.90(s,1H),7.66(m,2H),7.57(d,1H),7.38(s,2H),7.16(s,1H),6.60(m,1H) ,6.15(m,1H),5.77(m,1H),4.90(m,1H),4.75(m,1H),4.45-4.10(m,2H),3.85-2.95(m,2H),2.15-1.60(m,2H),1.42-1.10(m,2H).

[0333] Example 171

[0334] (Z)-4-Amino-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0335] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 171 (10 mg) was obtained from methyl (Z)-7-(5-bromopent-1-en-1-yl)-4-((3,5-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 171a (500 mg, 4.24 mmol) in a 2.9% yield. MS m / z (ESI): 453 [M+1]. +

[0336] 1H NMR(400MHz,MeOD)δ9.08(s,1H),8.88(s,1H),8.21–8.08(m,2H),7.96(s,1H),7.74(d,1H),7.33(s,1H),6.59 (d,1H),6.08(td,1H),5.18(d,1H),4.56(d,1H),3.65–3.44(m,2H),2.20(dt,1H),1.90(dq,2H),1.50(d,1H).

[0337] Alternatively, the following examples are prepared using the following method:

[0338] Example 173

[0339] (Z)-4-Amino-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,9,10,11,12-hexahydro-13H-azo[3,4-g]furo[3,4-c]quinolin-13-one

[0340] Step 1: Methyl 7-[(Z)-5-bromopenta-1-enyl]-4-[(2,4-dimethoxyphenyl)methylamino]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 173a (0.7 g, 1.29 mmol) was dissolved in acetonitrile (20 mL). [5-(trifluoromethyl)-2-pyridyl]methanamine (273.27 mg, 1.55 mmol), potassium carbonate (536.06 mg, 3.88 mmol), and sodium iodide (387.58 mg, 2.59 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction system was reacted at 80°C for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (100 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to give 173b (329 mg, 516.76 μmol) in a 40.0% yield. MS m / z (ESI): 637 [M+1] +

[0341] Step 2: 173b (329 mg, 516.76 μmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL). Lithium hydroxide monohydrate (65.05 mg, 1.55 mmol) was added, and the reaction system was reacted at 50°C for 3 hours. The reaction solution was concentrated to remove the organic phase, adjusted to neutrality with 2N hydrochloric acid, extracted with dichloromethane (with 10% methanol), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 173c (220 mg, 353.34 μmol) in a 68.4% yield. MS m / z (ESI): 623 [M+1] +

[0342] Step 3: 173c (210 mg, 337.28 μmol) was dissolved in N,N-dimethylformamide (20 mL). N,N-diisopropylethylamine (65.38 mg, 505.92 μmol, 88.12 μL) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.87 mg, 505.92 μmol) were added. The reaction system was stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 173d (188 mg, 310.94 μmol) in a 92.2% yield. MS m / z (ESI): 604 [M+1]. +

[0343] Step 4: 173d (188 mg, 310.94 μmol) was added to trifluoroacetic acid (10 mL), and the reaction system was reacted at 80°C for 1 hour. The reaction solution was adjusted to pH 8-9 with aqueous sodium bicarbonate solution, extracted with dichloromethane (with 10% methanol), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was reversely prepared to give Example 173 (13.4 mg, 29.49 μmol) in a 9.5% yield. MS m / z (ESI): 454 [M+1] +

[0344] 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.59(s,2H),8.24(dd,1H),7.74(s,1H),7.69(d,1H),7.52(s,1H),6.62(d,1H),6.07(d,1 H),5.46(dd,2H),5.13-4.99(m,3H),4.53(d,1H),2.21-2.08(m,1H),2.05-1.87(m,1H),1.70(d,2H),1.40(s,1H),1.27(d,1H)

[0345] Example 176

[0346] 4-Amino-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolidinone[8,7-g]quinoxalin-13(7H)-one

[0347] Referring to steps 5 to 8 of Example 14, methyl 7-((3-bromopropoxy)methyl)-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 14e (220 mg, 0.41 mmol) was used to obtain Example 176 (10 mg) in a 5.3% yield. MS m / z (ESI): 457 [M+1]. +

[0348] 1 H NMR(400MHz,DMSO-d6)δ9.20(d,1H),9.02–8.97(m,1H),8.24(dd,1H),8.09(s,1H),7.91(d,1H), 7.80(d,1H),7.40(d,3H),5.21(d,1H),4.65(d,1H),4.56–4.43(m,2H),3.50(t,4H),1.25(d,2H).

[0349] Alternatively, the following examples are prepared using the following method:

[0350] Example 177

[0351] 4-Amino-9-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one

[0352] Step 1: Dissolve 7,7-dimethyl-4-[(2,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinazoline-8-carboxylate 177a (4 g, 8.49 mmol), [3-(1,3-dioxoisoindolin-2-yl)-1-methylpropoxy]methylboronic acid (3.53 g, 12.73 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.85 g, 2.55 mmol), and potassium phosphate (5.40 g, 25.46 mmol) in dioxane (50 mL) and water (10 mL). The atmosphere was purged with nitrogen three times and stirred at 110°C for 16 hours. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (60 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to give 177b (3.5 g) in 66.1% yield. MS m / z (ESI): 624 [M+1] +

[0353] Step 2: 177b (500 mg, 801.73 μmol) was dissolved in ethanol (10 mL) and hydrazine hydrate (141.65 mg, 2.41 mmol, 85% purity) was added. The reaction was continued at 80°C for 16 hours. The mixture was cooled to room temperature, filtered, and the solid was dried to afford 177c (210 mg) in a 53.1% yield. MS m / z (ESI): 494 [M+1] +

[0354] Step 3: 177c (1 g, 2.03 mmol) and 5-trifluoromethylpyridine-2-carbaldehyde (425.75 mg, 2.43 mmol) were dissolved in methanol (50 mL). Acetic acid (243.35 mg, 4.05 mmol) and sodium cyanoborohydride (381.96 mg, 6.08 mmol) were then added. The reaction was allowed to proceed at 25°C for 16 h. The mixture was quenched with water and extracted with ethyl acetate (60 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 177d (400 mg) in a 30.2% yield. MS m / z (ESI): 525 [M+1]. +

[0355] Step 4: 177d (32.6 mg, 49.95 μmol) was dissolved in tetrahydrofuran (1 mL), water (1 mL), and methanol (1 mL). Lithium hydroxide (10.48 mg, 249.75 μmol) was added, and the reaction system was reacted at 25°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (5 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 177e (31 mg) in a 97.1% yield. MS m / z (ESI): 639 [M+1] +

[0356] Step 5: 177e (451.8 mg, 707.45 μmol) and N,N-diisopropylethylamine (548.58 mg, 4.24 mmol, 739.33 μL) were dissolved in N,N-dimethylformamide (10 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (533.80 mg, 1.41 mmol) was added, and the reaction system was reacted at 25°C for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (80 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 177f (430 mg) in a 97.9% yield. MS m / z (ESI): 621 [M+1]. +

[0357] Step 6: 177f (400 mg, 644.52 μmol) was dissolved in trifluoroacetic acid (8 mL) and the reaction system was incubated at 80°C for 0.5 h. LCMS indicated completion of the reaction. The reaction solution was then dried to afford the crude product, which was purified by preparative liquid chromatography to afford Example 177 (205.8 mg) in a 67.8% yield. MS m / z (ESI): 471 [M+1]. +

[0358] 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.00(d,1H),8.29–8.19(m,1H),8.07(s,1H),7.94(s,1H),7.78(dd,1H),7.48(s,2H),7.39(d,1H),5 .22(dd,J=16.1,7.2Hz,1H),4.85(dd,1H),4.52(dd,1H),4.32(dd,1H),3.43(d,2H),3.23(d,1H),1.68(dd,1H),1.18(s,1H),1.12(t,3H).

[0359] Example 178

[0360] 4-Amino-12-((5-trifluoromethylpyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolino[7,8-g]quinolin-13(1H)-one

[0361] Referring to the synthesis method of Example 14, 3-(benzyloxy)propan-1-ol 178a (1 g, 6 mmol) was used to obtain Example 178 (25 mg) in a 0.9% yield. MS m / z (ESI): 459 [M+1] +

[0362] 1 H NMR(400MHz,DMSO-d6)δ8.97(d,1H),8.24(dd,1H),7.76(d,1H),7.61(s,1H),7.52(s,1H),5.42(s,2H),5.19(d,1H), 5.06(s,2H),4.74(d,1H),4.58(d,1H),4.45(d,1H),3.81(d,1H),3.44(m,1H),3.26(m,2H),1.91(m,1H),1.23(d,1H).

[0363] Example 184

[0364] 4-amino-3-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinoxalin-13(1H)-one

[0365] Referring to the synthesis of Example 178, methyl 2-methyl-4-oxotetrahydrofuran-3-carboxylate 184a (500 mg, 3.16 mmol) was prepared by coupling, deprotection, bromination, substitution, hydrolysis, ring closure, and deprotection steps to afford Example 184 (12.5 mg) in a 0.6% yield. MS m / z (ESI): 473 [M+1]. +

[0366] 1 H NMR(400MHz,DMSO-d6)δ8.96(d,1H),8.26–8.22(m,1H),7.75(m,1H),7.50(s,1H),7.38(s,1H),6.56(s,2H),5.47–5.24 (m,4H),5.19(m,1H),4.71(m,1H),4.53(m,1H),4.43(d,1H),3.77(d,1H),3.23(d,2H),2.03–1.88(m,2H),1.40(d,3H).

[0367] Example 184-P1

[0368] (R)-4-amino-3-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinoxalin-13(1H)-one

[0369] first step

[0370] Compound 184i was separated by chiral preparative HPLC to give 184-P1a (200 mg) and 184-P2a (220 mg). MS m / z (ESI): 561 [M+1] +

[0371] From step 8 to step 11 of Reference Example 14, 184-P1a (200 mg, 0.394 mmol) was used to obtain Example 184-P1 (22 mg) through substitution, hydrolysis, ring closure, and deprotection. MS m / z (ESI): 473 [M+1] +

[0372] 1HNMR(400MHz,DMSO-d6)δ8.96(d,1H),8.26–8.22(m,1H),7.75(m,1H),7.50(s,1H),7.38(s,1H),6.56(s,2H),5.47–5.2 4(m,4H),5.19(m,1H),4.71(m,1H),4.53(m,1H),4.43(d,1H),3.77(d,1H),3.23(d,2H),2.03–1.88(m,2H),1.40(d,3H).

[0373] Example 184-P2

[0374] (S)-4-Amino-3-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinoxalin-13(1H)-one

[0375] Referring to the preparation of Example 184-P1, Example 184-P2 (18 mg) was obtained from 184-P2a (220 mg, 0.394 mmol) through substitution, hydrolysis, ring closure, and deprotection steps. MS m / z (ESI): 473 [M+1] +

[0376] 1 HNMR(400MHz,DMSO-d6)δ8.96(d,1H),8.26–8.22(m,1H),7.75(m,1H),7.50(s,1H),7.38(s,1H),6.56(s,2H),5.47–5.2 4(m,4H),5.19(m,1H),4.71(m,1H),4.53(m,1H),4.43(d,1H),3.77(d,1H),3.23(d,2H),2.03–1.88(m,2H),1.40(d,3H).

[0377] Example 190

[0378] 4-Amino-1-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,7,9,10,11,12-hexahydro-13H-[1,5]oxazolo[7,8-g]pyrazolo[4,3-c]quinolin-13-one

[0379] Referring to the preparation method of Example 165, Example 190 (17 mg) was obtained from methyl 4-amino-2-bromobenzoate 190a (5 g, 21.73 mmol) in a yield of 2.6%. MS m / z (ESI): 471 [M+1] +

[0380] 1 H NMR(400MHz,DMSO-d6)δ8.97(d,1H),8.38(s,1H),8.26(dd,1H),8.07(s,1H),7.80(d,1H),7.59(s,2H),5.20 (d,1H),4.75(d,1H),4.55(dd,2H),3.81(dt,1H),3.54–3.36(m,3H),3.26(d,3H),1.90(q,1H),1.25(d,1H).

[0381] Example 214

[0382] 4-amino-12-(4-(pentafluoro-λ 6 -mercapto)benzyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolidinone[8,7-g]quinoxalin-13(7H)-one

[0383] Referring to the synthesis of Example 14, Example 214 (10 mg) was obtained from methyl 7-((3-bromopropoxy)methyl)-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 14e (220 mg, 0.41 mmol) in a 5.3% yield. MS m / z (ESI): 514 [M+1]. +

[0384] 1 H NMR(400MHz,DMSO-d6)δ9.21(d,1H),8.10(s,1H),7.93(d,3H),7.69(d,2H),7.40(d,3H),5.24(d,1H),4. 57(dd,2H),4.31(d,1H),3.75(d,1H),3.46(t,1H),3.29(s,1H),3.10(d,1H),1.92(dd,1H),1.20(d,1H).

[0385] The preparation of the following examples refers to Example 62:

[0386] Alternatively, the following examples are prepared using the following method:

[0387] Example 250

[0388] 4-Amino-11-(5-trifluoromethylpyridin-2-yl)methyl-8,9,10,11-tetrahydroazin[4,3-g]imidazo[1,5-a]quinoxalin-12(7H)-one

[0389] Referring to the synthesis method of steps 4 to 9 of Example 62, (Z)-methyl 7-(5-bromobut-1-en-1-yl)-4-((3,5-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 157c was used to obtain Example 250 (15 mg) in a 7.4% yield. MS m / z (ESI): 441 [M+1]. +

[0390] 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.97(d,1H),8.32(s,1H),8.28(s,1H),8.24(dd,1H),7.66(d,1H),7.42(s,1H),5.1 7(d,1H),4.65(d,1H),3.24(d,2H),2.95(dd,1H),2.76(t,1H),2.19–2.08(m,1H),1.84(d,1H),1.67(d,1H),1.46(d,1H).

[0391] Or the synthesis of the following examples refers to the following preparation method:

[0392] Example 268

[0393] 4-Amino-12-(6-trifluoromethyl-2,3-dihydrobenzofuran-3-yl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazepino[8,7-g]quinoxalin-13(7H)-one

[0394] Following the method of Example 14, methyl 7-((3-bromopropoxy)methyl)-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 14e (300 mg, 0.55 mmol) and 6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (168 mg, 0.83 mmol) were reacted to afford Example 268 (20 mg) in a 7.5% yield. MS m / z (ESI): 484 [M+1] +

[0395] 1 H NMR(400MHz,DMSO-d6)δ8.39(dd,2H),8.05(s,1H),7.52(d,1H),7.49–7.36(m,2H),7.29(dq,1H ),5.15(td,1H),4.84(d,2H),4.57(dd,1H),4.32(m,1H),3.71(m,1H),3.55(m,3H),1.90(m,2H).

[0396] Example 270

[0397] 4-Amino-1-methyl-12-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1,7,9,10,11,12-hexahydro-13H-[1,5]oxazolidinone[7,8-g]pyrazolo[4,3-c]quinolin-13-one

[0398] Step 1: Disperse methyl 4-amino-2-bromo-formate 270a (10.00 g, 43.67 mmol) and N-iodosuccinimide (10.13 g, 45.00 mmol) in 100 mL of acetonitrile. Stir the reaction at 25°C for 16 hours. Filter the reaction mixture to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System A to afford 270b (14.00 g) in a 90.3% yield. MS m / z (ESI): 356 [M+1] +

[0399] Step 2: Disperse 270b (9.00 g, 25.35 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol (10.55 g, 50.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.86 g, 2.54 mmol), and potassium phosphate (10.75 g, 50.70 mmol) in 1,4-dioxane (150 mL) and water (30 mL). Stir and react at 80°C for 16 hours. The reaction mixture was filtered to remove insoluble material. The filtrate was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 270c (6.50 g) in 83.0% yield. MS m / z (ESI): 310 [M+1]. +

[0400] Step 3: Disperse 270c (6.50 g, 21.04 mmol) and potassium N,N'-carbonyldiimidazole phosphate (6.82 g, 42.08 mmol) in 65 mL of N-methylpyrrolidone. Stir and react at 150°C for 1 hour. Pour the reaction solution into 650 mL of water. A solid precipitates and is filtered to give 270d (5.71 g) in 81.0% yield. MS m / z (ESI): 336 [M+1] +

[0401] Step 4: Disperse 270d (5.71 g, 17.04 mmol), 2,4-dimethoxybenzylamine (5.69 g, 34.08 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.18 g, 34.08 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (15.06 g, 34.08 mmol) in 50 mL of dimethyl sulfoxide. Stir and react at 25°C for 1 hour. The reaction solution was poured into 500 mL of water. A solid precipitated and was filtered to give 270e (6.41 g) in a 77.7% yield. MS m / z (ESI): 485 [M+1]. +

[0402] The synthesis method of reference example 14 was used to obtain example 270 (35 mg) from 270e (500 mg, 0.41 mmol) in a yield of 6.8%. MS m / z (ESI): 498 [M+1] +

[0403] 1H NMR(400MHz,DMSO-d6)δ8.52(s,2H),8.25–7.93(m,1H),7.77–7.58(m,2H),7.29(dd,2H),6.06–5.79(m,1H),4.99–4 .77(m,3H),4.54–4.44(m,4H),3.82(dd,1H),3.42–3.39(m,2H),3.30–3.10(m,2H),1.67–1.24(m,1H),1.09(dd,1H).

[0404] Example 298

[0405] 4-Amino-12-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one

[0406] Referring to the synthesis of Example 62, Example 298 (25 mg) was obtained from methyl 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 298a (200 mg, 0.37 mmol) in a 13.1% yield. MS m / z (ESI): 501 [M+1]. +

[0407] 1 H NMR(400MHz,MeOD)δ9.32(s,1H),8.68(s,1H),8.37(d,2H),8.06(m,1H),7.82(m,1H),7.57(s,1H),7.54-7.46(m,1H),7.19 -7.15(m,2H),5.42(d,1H),4.90-4.86(m,1H),4.59(d,1H),4.49(d,1H),3.97(d,1H),3.58-3.39(m,3H),2.23-2.02(m,2H).

[0408] Example 311

[0409] (Z)-4-((2,4-dimethoxybenzyl)amino)-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazocino[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one

[0410] Step 1: Dissolve 2-(trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 311a (3 g, 13.82 mmol) and hydroxylamine hydrochloride (960 mg, 13.82 mmol) in ethanol (30 mL) and sodium acetate (3.40 g, 41.45 mmol). The nitrogen atmosphere was purged three times and the system was reacted at 80°C for 1 hour. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (100 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 311b (3.10 g) in a 96.7% yield. MS m / z (ESI): 233 [M+1]. +

[0411] Step 2: Dissolve 311b (20.98 g, 90.37 mmol), zinc powder (59.08 g, 903.69 mmol), and ammonium chloride (48.34 g, 903.69 mmol) in ethanol (40 mL) and react at 50°C for 4 hours. Filter, concentrate, and slurry with dichloromethane to afford 311c (12.6 g) in a 63.9% yield. MS m / z (ESI): 219 [M+1] +

[0412] Step 3: 311d (20 g, 42.44 mmol) and cuprous iodide (1.62 g, 8.49 mmol) were dissolved in N,N-dimethylformamide (200 mL) and triethylamine (14.17 g, 140.04 mmol, 19.53 mL). The nitrogen atmosphere was evacuated three times, 3-butyn-1-ol (14.87 g, 212.18 mmol) and bistriphenylphosphine palladium dichloride (2.98 g, 4.24 mmol) were added, the nitrogen atmosphere was evacuated three times, and the system was reacted at 40 ° C for 16 hours. Cool to room temperature, concentrate, quench with water, extract with ethyl acetate (60 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to give 311e (19 g, crude product). MS m / z (ESI): 461 [M+1] +

[0413] Step 4: Dissolve 311e (1.8 g, 3.91 mmol) and Raney nickel (4.59 g, 78.18 mmol) in tetrahydrofuran (250 mL) and methanol (50 mL). The hydrogen atmosphere was evacuated three times and the reaction was carried out under a hydrogen balloon at 25°C for 2 h. Filter and concentrate to afford 311f (1.6 g, crude product). MS m / z (ESI): 463 [M+1] +

[0414] Step 5: Dissolve 311f (4.8 g, 10.38 mmol) in dichloromethane (50 mL), purge with nitrogen three times, and cool to 0°C. Triphenylphosphine (10.89 g, 41.51 mmol) and carbon tetrabromide (13.77 g, 41.51 mmol) are then added, and the system is reacted at 25°C for 2 hours. The mixture is concentrated. The residue is purified by silica gel column chromatography using eluent System B to afford (Z)-methyl 7-(4-bromobut-1-en-1-yl)-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 311 g (3 g) in a 55.2% yield. MS m / z (ESI): 525 [M+1]. +

[0415] Step 6: 311g (1.5g, 2.86mmol), 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (1.25g, 5.71mmol), and sodium iodide (855.87mg, 5.71mmol) were dissolved in acetonitrile (40mL), and ground potassium carbonate (1.18g, 8.57mmol) was added. The nitrogen atmosphere was purged three times, and the reaction system was reacted at 80°C for 15 hours. The mixture was quenched with water, extracted with ethyl acetate (80mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system A to give 311h (252mg) in a yield of 13.5%. MS m / z (ESI): 662[M+1] +

[0416] Step 7: 311h (252 mg, 380.86 μmol) was dissolved in tetrahydrofuran (2 mL), water (2 mL) and methanol (2 L), and lithium hydroxide (63.92 mg, 1.52 mmol) was added. The nitrogen atmosphere was evacuated three times, and the reaction system was reacted at 25°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 311i (242 mg, crude product). MS m / z (ESI): 648 [M+1] +

[0417] Step 8: 311i (240 mg, 370.57 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (279.61 mg, 741.15 μmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (287.36 mg, 2.22 mmol, 387.28 μL) was added. The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 25°C for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 311j (195 mg) in 84% yield. MS m / z (ESI): 630 [M+1]. +

[0418] Step 9: 311j (190 mg, 301.29 μmol) was dissolved in trifluoroacetic acid (5 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 90°C for 0.5 h. LCMS indicated completion of the reaction. The reaction solution was then spin-dried to afford the crude product, which was purified by preparative liquid chromatography to afford Example 311 (76 mg) in a 52.5% yield. MS m / z (ESI): 481 [M+1]. +

[0419] 1 H NMR(400MHz,DMSO-d6)δ9.18(d,1H),8.22(s,1H),8.15-8.05(m,1H),8.01-7.89(m,1H),7.84(dd,1H),7.62(s,2H),7.18(d,1H) ,6.59(ddd,1H),5.91(m,1H),5.55(d,1H),4.94-4.74(m,2H),4.34-4.12(m,2H),3.80-3.62(m,2H),3.16(d,1H),2.76(td,1H).

[0420] Example 311-P1 & 311-P2

[0421] Example 311 (76 mg, 0.16 mmol) was separated by chiral preparative HPLC to give rel-(S)-(Z)-4-((2,4-dimethoxybenzyl)amino)-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazocino[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one 311. -P1 (35 mg, 46.1% yield) and rel-(R)-(Z)-4-((2,4-dimethoxybenzyl)amino)-13-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-10,11,12,13-tetrahydroazocino[4,3-g]imidazo[1,5-a]quinoxalin-14(9H)-one 311-P2 (36 mg, 47.3% yield).

[0422] 311-P1(t R :5.346min): 1 H NMR(400MHz,DMSO-d6)δ9.40(d,1H),9.21(br s,2H),8.38(s,1H),8.30(d,1H),8.14-7.75(m,2H),7.29(d,1H),6.62(dd,1H),6.01(m,1 H),5.56(s,1H),4.85(qd,2H),4.26(m,2H),3.77(m,1H),2.80(m,1H),2.50-1.78(m,2H).

[0423] 311-P2(t R :4.447min): 1 H NMR(400MHz,DMSO-d6)δ9.40(d,1H),9.21(br s,2H),8.38(s,1H),8.30(d,1H),8.14-7.75(m,2H),7.29(d,1H),6.62(dd,1H),6.01(m,1 H),5.56(s,1H),4.85(qd,2H),4.26(m,2H),3.77(m,1H),2.80(m,1H),2.50-1.78(m,2H).

[0424] Example 313

[0425] 4-Amino-11-(1-(5-trifluoromethylpyridin-2-ethyl)-10,11-dihydroazocino[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one

[0426] Referring to the synthesis of Example 62, Example 313 (102 mg) was obtained from Z-7-(6-bromopent-1-en-1-yl)-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 157d (500 mg, 0.55 mmol) in a 25.1% yield. MS m / z (ESI): 453 [M+1]. +

[0427] Example 313-P1 & 313-P2

[0428] Example 313 (102 mg, 0.23 mmol) was separated by chiral preparative HPLC to give rel-(R,Z)-4-amino-11-(1-(5-trifluoromethylpyridine-2-ethyl)-10,11-dihydroazocine[4,3-g]imidazo[1,5-a]quinoxaline-12(9H)-one 313-P1 (38 mg) in a 37.2% yield and rel-(S,Z)-4-amino-11-(1-(5-trifluoromethylpyridine-2-ethyl)-10,11-dihydroazocine[4,3-g]imidazo[1,5-a]quinoxaline-12(9H)-one 313-P2 (42 mg) in a 41.2% yield.

[0429] 313-P1(t R :1.100min): 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.97(s,1H),8.21(d,1H),8.10(s,1H),7.89(s,1H),7.69(dd,1H),7.44(s,2H ),7.15(d,1H),6.57(dd,1H),5.90–5.47(m,2H),3.78(dt,1H),3.56–3.38(m,1H),2.47–2.21(m,2H),1.73(dd,3H).

[0430] 313-P2(t R :1.490min): 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.21(d,1H),8.10(s,1H),7.89(s,1H),7.69(dd,1H),7.43(s,2 H),7.15(d,1H),6.57(dd,1H),5.94–5.47(m,2H),3.91–3.44(m,2H),2.45–1.98(m,2H),1.73(t,3H).

[0431] Example 325

[0432] (Z)-4-Amino-11-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-10,11-dihydroazo[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one

[0433] Step 1: 7-Bromo-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 325a (20 g, 42.44 mmol) and cuprous iodide (1.62 g, 8.49 mmol) were dissolved in N,N-dimethylformamide (200 mL) and triethylamine (14.17 g, 140.04 mmol, 19.53 mL). The atmosphere was purged with nitrogen three times, and 3-butyn-1-ol (14.87 g, 212.18 mmol) and bistriphenylphosphine palladium dichloride (2.98 g, 4.24 mmol) were added. The atmosphere was purged with nitrogen three times, and the system was reacted at 40°C for 16 hours. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (60 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 325b (19 g, crude product). MS m / z(ESI):461[M+1] +

[0434] Step 2: Dissolve 325b (2.2 g, 4.78 mmol) in 100 mL of tetrahydrofuran, add 100 mL of methanol, and add 4.4 g of Raney Ni. Replace the atmosphere with hydrogen three times and allow to react at room temperature for 3 h. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 325c (1.7 g) in a 76.9% yield. MS m / z (ESI): 463 [M+1] +

[0435] Step 3: Dissolve 325c (1.6 g, 3.46 mmol) in 20 mL of dichloromethane, add triphenylphosphine (2.27 g, 8.65 mmol), and replace the atmosphere with nitrogen three times. Add carbon tetrabromide (2.87 g, 8.65 mmol) under nitrogen, and react at room temperature for 16 h. The reaction solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography with eluent System B to afford 325d (1.6 g) in 87.9% yield. MS m / z (ESI): 526 [M+1] +

[0436] Step 4: Dissolve 325d (1.6 g, 2.86 mmol) in 20 mL of tetrahydrofuran, add N,N-diisopropylethylamine (738 mg, 5.71 mmol) and 6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (1.16 g, 5.71 mmol), and heat to 65°C for 48 h. The reaction solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography with eluent B to afford 325e (1.1 g) in a 59.5% yield. MS m / z (ESI): 648.5 [M+1] +

[0437] Step 5: Dissolve 325e (1.1 g, 1.70 mmol) in 10 mL of tetrahydrofuran, add 2 mL of water, and lithium hydroxide monohydrate (163 mg, 6.79 mmol). React at room temperature for 16 h. The reaction solution is concentrated to remove the solvent, and the residual solution is adjusted to pH 5-6 with 1N HCl. The solution is extracted three times with ethyl acetate and concentrated. The residue is purified by silica gel column chromatography with eluent B to afford 325f (1.0 g) in a 92.9% yield. MS m / z (ESI): 634 [M+1] +

[0438] Step 6: Dissolve 325f (105 mg, 0.165 mmol) in 5 mL of N,N-dimethylformamide, add N,N-diisopropylethylamine (107 mg, 0.828 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126 mg, 331 mmol), and react at room temperature for 16 h. The reaction solution was slowly added to water to quench, extracted three times with ethyl acetate, and concentrated to yield 325 g (100 mg), yield: 98.0%. MS m / z (ESI): 616 [M+1] +

[0439] Step 7: Dissolve 325 g (100 mg, 0.162 mmol) in 5 mL of trifluoroacetic acid, heat to 80°C, and react for 0.5 h. The reaction solution was concentrated, and the residue was purified by chromatography using eluent C to afford Example 325 (38 mg) in a 50.2% yield. MS m / z (ESI): 466 [M+1] +

[0440] 1H NMR(400MHz,DMSO-d6)δ9.44(d,3H),8.58-8.16(m,2H),7.58(d,0.5H),7.45(d,0.5H),7.36-7.21(m,2H),6.60(t,1H),6.09(d,0.5 H),6.02-5.89(m,1H),5.68(dd,0.5H),4.88(dt,1H),4.65(m,1H),3.70(d,1H),3.41(dd,0.5H),3.12(d,0.5H),2.43-2.21(m,1H).

[0441] Example 331

[0442] 4-Amino-10-((5-(trifluoromethyl)pyridin-2-yl)methyl)-9,10-dihydro-11H-azepin[4,3-g]imidazo[1,5-a]quinoxalin-11-one

[0443] Step 1: 5-Trifluoromethyl-2-pyridinecarboxaldehyde 331a (1.5 g, 8.57 mmol), 2-propyn-1-amine (471.81 mg, 8.57 mmol), sodium cyanoborohydride (1.61 g, 25.70 mmol), and acetic acid (102.88 mg, 1.71 mmol) were dissolved in methanol (20 mL) and reacted at 20°C for 1 hour. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (80 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product 331b (1.69 g) was obtained and used directly in the next step without purification. MS m / z (ESI): 215 [M+1] +

[0444] Step 2: Dissolve 331b (1.69 g, 7.89 mmol), di-tert-butyl dicarbonate (3.44 g, 15.78 mmol), 4-dimethylaminopyridine (192.79 mg, 1.58 mmol), and triethylamine (2.40 g, 23.67 mmol) in dichloromethane (20 mL) and concentrate. The residue was purified by silica gel column chromatography using eluent System B to afford 331c (1.05 g) in a 42.2% yield. MS m / z (ESI): 315 [M+1] +

[0445] Step 3: Dissolve 62d (320 mg, 0.68 mmol), N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propyl-2-ynyl-1-tert-butoxycarbonyl carbonate (640.20 mg, 2.04 mmol), dichlorobis(tricyclohexylphosphine)palladium (50.12 mg, 67.90 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (64.73 mg, 135.79 μmol), and cesium carbonate (663.66 mg, 2.04 mmol) in dioxane (6 mL). The system was reacted at 100°C for 3 hours. The mixture was cooled to room temperature, concentrated, quenched with water, extracted with ethyl acetate (60 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 331d (180 mg) in a yield of 37.5%. MS m / z(ESI):705[M+1] +

[0446] Step 4: Dissolve 331d (100 mg, 0.14 mmol) and Raney nickel (100 mg) in methanol (10 mL) and tetrahydrofuran. The hydrogen atmosphere was evacuated three times and the reaction was carried out under a hydrogen balloon at 25°C for 0.5 h. Filter and concentrate to afford 331e (0.1 g, crude product). MS m / z (ESI): 707 [M+1] +

[0447] Step 5: 331e (0.1 g, 0.14 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL). The system was reacted at 25°C for 0.5 h and concentrated to afford 331f (100 mg, crude product). MS m / z (ESI): 607 [M+1] +

[0448] Step 6: Dissolve the crude product of 331f (100 mg) and LiOH (10 mg, 0.42 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction system was incubated at 50°C for 2 hours. Concentrate. The residue was purified by reverse-phase column chromatography using eluent System A to afford 331 g (22 mg) in a 26.5% yield. MS m / z (ESI): 593 [M+1]. +

[0449] Step 7: Dissolve 331 g (22 mg, 0.037 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28 mg, 0.074 mmol) in N,N-dimethylformamide (3 mL). Add N,N-diisopropylethylamine (14.3 mg, 8.76 mmol, 19 μL) and react at 25°C for 16 hours. The system was concentrated to dryness, and the residue was purified by silica gel column chromatography with eluent System C to afford 331h (18 mg) in an 84.6% yield. MS m / z (ESI): 575 [M+1]. +

[0450] Step 8: 331h (18 mg, 0.031 mmol) was dissolved in trifluoroacetic acid (2 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 90°C for 0.5 hours. The product was concentrated, and the residue was purified by silica gel column chromatography using eluent System A to afford Example 331 (4.2 mg) in a 31.9% yield. MS m / z (ESI): 425 [M+1]. +

[0451] 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.96–8.94(m,1H),8.62(s,1H),8.22(m,1H),7.93(s ,1H),7.59–7.54(m,3H),7.37(s,1H),6.97(m,1H),6.41(m,1H),4.96(s,2H),3.85(m,2H).

[0452] Example 352

[0453] (Z)-4-Amino-12-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0454] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 352 (32 mg) was obtained from (Z)-7-(5-bromopent-1-en-1-yl)-4-(3,5-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 352a (500 mg, 0.93 mmol) in a 7.4% yield. MS m / z (ESI): 467 [M+1]. +

[0455] 1H NMR(400MHz,MeOD)δ9.11–9.06(m,1H),8.91–8.87(m,1H),8.13(dd,1H),8.07(d,1H),8.01(s,1H),7.79(d,1H),7.30(d,1H), 6.56(dd,1H),6.09(dtd,1H),5.42(dq,1H),3.76–3.68(m,1H),3.62–3.49(m,1H),2.16(ddd,1H),1.86(dd,4H),1.49(dt,2H).

[0456] Example 362

[0457] (Z)-4-amino-9-methyl-12-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0458] Step 1: 3-Methyltetrahydrofuran-2-one 362a (7 g, 69.92 mmol) was dissolved in dichloromethane (70 mL). The atmosphere was purged with nitrogen three times. Diisobutylaluminum hydride (12.84 g, 90.90 mmol, 16.08 mL) was added dropwise at -78°C, and the reaction mixture was stirred at -78°C for 1 hour. Sodium tartrate solution was added to the reaction mixture and stirred for 2 hours. 500 mL of water was added to separate the mixture, and the aqueous phase was extracted with 500 mL of tert-butyl methyl ether. The organic phase was dried over anhydrous sodium sulfate and concentrated at 20°C. The intermediate was used directly in the next step. The intermediate was dissolved in methanol (70 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (14.78 g, 76.91 mmol) and potassium carbonate (19.33 g, 139.84 mmol) were added at room temperature. The atmosphere was purged with nitrogen three times, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was added with silica gel powder and concentrated at 20°C. The sample was purified by column chromatography (PE:EA=62:38) to give 362b (3.8 g, 38.72 mmol) in a yield of 55.4%.

[0459] Step 2: Methyl 7-bromo-4-[(2,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinoxaline-8-carboxylate 362c (10 g, 21.22 mmol) and 362b (3.8 g, 38.72 mmol) were dissolved in DMF (100 mL). Bis(triphenylphosphine)palladium(II) chloride (1.49 g, 2.12 mmol), cuprous iodide (808.18 mg, 4.24 mmol), and triethylamine (7.09 g, 70.02 mmol, 9.77 mL) were added sequentially at room temperature. The reaction was stirred at 40°C overnight. LCMS analysis showed the disappearance of the starting material and the formation of the product. The reaction mixture was extracted three times with 1 L of water and 300 mL of EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 94:6) to afford 362d (10 g, 20.47 mmol) in a 96.5% yield. MS m / z (ESI): 489 [M+1] +

[0460] Step 3: 362d (10 g, 20.47 mmol) was dissolved in tetrahydrofuran (50 mL) and methanol (50 mL). Raney nickel (1.27 g, 21.57 mmol) was added at room temperature and hydrogen was replaced three times. The reaction solution was stirred at room temperature overnight. LCMS monitoring showed that the starting material disappeared and the product was formed. The reaction solution was directly filtered and the filtrate was concentrated to obtain crude product 362e, which was used directly in the next step. MS m / z (ESI): 491 [M+1] +

[0461] Step 4: 362e was dissolved in dichloromethane (10 mL). Carbon tetrabromide (2.89 g, 8.72 mmol) and triphenylphosphine (2.29 g, 8.72 mmol) were added sequentially at room temperature. The reaction mixture was stirred for 2 hours. LCMS monitoring showed the disappearance of the starting material and the formation of the product. The reaction mixture was extracted three times with 100 mL of water and 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 94:6) to afford 362f (1.1 g, 2.11 mmol). The two-step yield was 96.7%. MS m / z (ESI): 553 [M+1]. +

[0462] Step 5: 362f (3 g, 5.75 mmol) was dissolved in acetonitrile (10 mL). Potassium carbonate (2.39 g, 17.26 mmol) and sodium iodide (862.37 mg, 5.75 mmol) were added at room temperature. The nitrogen atmosphere was replaced three times, and the reaction solution was stirred at 80°C overnight. LCMS monitoring showed the disappearance of the starting material and the formation of the product. The reaction solution was extracted three times with 100 mL of water and 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 95:5) to give 362g (2 g, 3.03 mmol) in a yield of 52.8%. MS m / z (ESI): 691 [M+1] +

[0463] Step 6: Dissolve 362g (500mg, 759.06μmol) in water (2mL), tetrahydrofuran (2mL) and methanol (2mL), and add lithium hydroxide (18.18mg, 759.06μmol) at room temperature. The reaction solution was stirred at room temperature overnight. The disappearance of the starting material and the formation of the product were monitored by LCMS. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5-6, and ethyl acetate was added for extraction. The organic phase was dried and concentrated to give the crude product 362h (460mg), which was used directly in the next step. MS m / z (ESI): 677[M+1] +

[0464] Step 7: 362h (600 mg, 930.69 μmol) was dissolved in N,N-dimethylformamide (10 mL). (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (702.24 mg, 1.86 mmol) was added at room temperature. The nitrogen atmosphere was replaced three times, and the reaction solution was stirred at room temperature for 24 hours. LCMS monitoring showed the disappearance of the starting material and the formation of the product. The reaction solution was extracted three times with 200 mL of water and 100 mL of ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 95:5) to afford 362i (320 mg, 510.64 μmol) in a 54.9% yield. MS m / z (ESI): 659 [M+1]. +

[0465] Step 8: 362i (300 mg, 478.72 μmol) was dissolved in trifluoroacetic acid (8 mL), the nitrogen atmosphere was replaced three times, and the reaction mixture was stirred at 90°C for 0.5 h. LCMS monitoring showed the disappearance of the starting material and the formation of the product. The reaction mixture was added with ice water, and the pH was adjusted to a weak alkaline state with sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was subjected to alkaline treatment to afford Example 362 (30 mg) in a yield of 12.3%. MS m / z (ESI): 509 [M+1] +

[0466] 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.13(m,2H),8.04(br s,1H),7.85(t,2H),7.18(m,2H),6.48(dd,1H),5.53(m,1H),4.82(m,2H),4. 22(m,2H),3.77(m,1H),3.55(m,2H),1.23(m,3H),0.97(d,1H),0.85(d,2H).

[0467] Example 374

[0468] 4-Amino-12-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolidinone[8,7-g]quinoxalin-13(7H)-one

[0469] Step 1: Dissolve 2-acetyl-5-trifluoromethylpyridine 374a (5 g, 26.44 mmol) in 100 mL of ethanol. Add hydroxylamine hydrochloride (3.67 g, 52.87 mmol) and sodium acetate (8.67 g, 405.74 mmol). Stir the reaction at 80°C for approximately 3 hours. Add water (200 mL) to the reaction mixture, extract with ethyl acetate (200 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System B to afford 374b (4.8 g) in 88.9% yield. MS m / z (ESI): 205 [M+1]. +

[0470] Step 2: 374b (4.7 g, 23.02 mmol) was dissolved in 60 mL of trifluoroacetic acid, and zinc powder (7.5 g, 115.11 mmol) was added. The reaction was heated at 80°C for 3 hours. The reaction mixture was filtered and distilled under reduced pressure. The pH was adjusted to alkaline by adding saturated sodium hydroxide solution, and then extracted with dichloromethane (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System C to afford 374c (1.9 g) in a 43.4% yield. MS m / z (ESI): 595 [M+1]. +

[0471] Referring to the fifth to eighth steps of Example 14, Example 374 (2 mg) was obtained from 374c (70 mg, 0.36 mmol) in a yield of 1.2%. MS m / z (ESI): 471 [M+1]+

[0472] 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.96–8.92(m,1H),8.23(d,2H),8.17(d,1H),7.94(dd,1H),7.48(d,1H), 5.55(d,1H),4.75(dd,1H),4.52–4.46(m,1H),3.85–3.69(m,1H),3.22–3.06(m,4H),1.87(d,2H),1.77(d,2H).

[0473] Example 391

[0474] (Z)-4-Amino-12-(6-trifluoromethylpyridazin-3-yl)methyl-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0475] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 391 (9 mg) was obtained from 62 g (422 mg, 0.78 mmol) of methyl (Z)-7-(6-bromopent-1-en-1-yl)-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate in a 2.5% yield. MS m / z (ESI): 454 [M+1]. +

[0476] 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.31(d,1H),8.25(s,1H),8.10(s,1H),8.05(d,1H),7.26(s,1H),6. 53(d,1H),5.98(td,1H),5.15(d,1H),4.87(d,1H),3.48(m,2H),2.13(dt,1H),1.75(m,2H),1.43(d,1H).

[0477] Example 414

[0478] 4-amino-12-((5-(pentafluoro-λ 6 (-mercapto)pyridin-2-yl)methyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolidinone[8,7-g]quinoxalin-13(7H)-one

[0479] Step 1: Disperse 5-mercapto-2-cyanopyridine 414a (10.00 g, 73.53 mmol) and sodium iodide (4.47 g, 30.00 mmol) in 200 mL of acetonitrile. Add ferric chloride (4.83 g, 30.00 mmol) at 25°C and stir at 25°C for 16 hours. Dilute the reaction mixture with 200 mL of dichloromethane and filter to remove insoluble matter. The filtrate is concentrated to dryness under reduced pressure and the resulting residue is purified by silica gel column chromatography with eluent System A to afford 414b (6.15 g) in a 62.0% yield. MS m / z (ESI): 271 [M+1]. +

[0480] Step 2: Disperse 414b (6.15 g, 22.78 mmol) and tetraethylammonium chloride (7.52 g, 45.56 mmol) in 150 mL of acetonitrile, and add silver difluoride (52.85 g, 364.48 mmol). Stir the reaction at 25°C for 16 hours. Filter the reaction mixture to remove insoluble matter. The filtrate is concentrated to dryness under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System A to afford 414c (1.57 g) in a 15.0% yield. MS m / z (ESI): 231 [M+1] +

[0481] Step 3: Disperse 414c (1.57 g, 6.83 mmol), di-tert-butyl dicarbonate (2.83 g, 13.00 mmol), and cobalt chloride (1.07 g, 8.20 mmol) in 30 mL of methanol. Add sodium borohydride (1.82 g, 47.81 mmol) portionwise at 0°C and stir at 25°C for 1 hour. Add 2 mL of water and 50 mL of dichloromethane to the reaction mixture, and remove insoluble matter by filtration. The filtrate is concentrated to dryness under reduced pressure, and the resulting residue is purified by silica gel column chromatography with eluent System A to afford 414d (1.65 g) in a 72.5% yield. MS m / z (ESI): 335 [M+1]. +

[0482] Step 4: Disperse 414d (1.65 g, 4.94 mmol) in 20 mL of hydrochloric acid (4 M, 1,4-dioxane solution). Stir and react at 25°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to afford 414e (1.10 g) in a 95.5% yield. MS m / z (ESI): 235 [M+1] +

[0483] Referring to the fifth to eighth steps of Example 14, Example 414 (29 mg) was obtained from 414e (350 mg, 1.50 mmol) in a yield of 3.8%. MS m / z (ESI): 515 [M+1] +

[0484] 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.13(s,1H),8.39(dd,1H),8.10(s,1H),7.99–7.38(m ,5H),5.18(d,1H),4.71–4.40(m,3H),3.80(d,1H),3.48(dd,3H),1.92(d,1H),1.26(d,1H).

[0485] Example 415

[0486] (Z)-4-Amino-12-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-9,10,11,12-tetrahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0487] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 415 (28 mg) was obtained from (Z)-7-(5-bromopent-1-en-1-yl)-4-(3,5-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 415a (500 mg, 0.93 mmol) in a 6.5% yield. MS m / z (ESI): 467 [M+1]. +

[0488] 1 H NMR(400MHz,DMSO-d6)δ9.24(d,1H),8.86(s,1H),8.21–8.12(m,2H),8.09–7.89(m,3H),7.21(s,1H),6.54(t,1H) ,6.18–5.92(m,1H),5.37(dd,1H),3.55(d,2H),2.14(t,1H),2.03(d,1H),1.77(dd,4H),1.48(s,1H),1.34(s,1H).

[0489] Example 416

[0490] (Z)-4-Amino-11-(5-trifluoromethylpyridin-2-yl)methyl-10,11-dihydroazin[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one

[0491] Referring to the ninth step of the method of Example 62, (Z)-4-(2,4-dimethoxybenzylamino)-1-(5-trifluoromethylpyridin-2-yl)methyl-10,11-dihydroazin[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one 250c (60 mg, 0.10 mmol) was used to obtain Example 416 (28 mg) in a 63.8% yield. MS m / z (ESI): 439 [M+1]. +

[0492] 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.96(d,1H),8.27(s,1H),8.26(broad s,2H),8.24(dd,1H),8.11(s,1H),7.64(d,1H),7.26(s,1H),6.59(d,1H),5.86– 5.77(m,1H),5.11(d,1H),4.65(d,1H),3.87(t,1H),2.70(td,1H),2.38(dt,1H)

[0493] Example 417

[0494] 4-Amino-13-((5-(trifluoromethyl)pyridin-2-yl)methyl)-10,11,12,13-tetrahydro-7H-imidazo[1,5-a][1,6]oxazino[3,4-g]quinoxalin-14(9H)-one

[0495] Referring to steps 6 to 9 of Example 62, Example 417 (7 mg) was obtained in a 1.6% yield from methyl 7-((3-bromopropoxy)methyl)-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 417a (500 mg, 0.89 mmol). MS m / z (ESI): 471 [M+1]. +

[0496] 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.01(s,1H),8.90(broad s,2H),8.33–8.22(m,2H),8.19(s,1H),7.81(d,J=8.3Hz,1H),7.52(s,1H),5.26(d,1H ),4.75(d,1H),4.48(t,1H),4.40(d,1H),3.66(t,2H),3.22(d,2H),2.04–1.61(m,4H)

[0497] Example 418

[0498] (Z)-4-amino-12-(6-trifluoromethylpyridazin-3-yl)methyl-9,10,11,12-tetrahydro-13H-azocino[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0499] Referring to the synthesis method of steps 6 to 9 of Example 62, (Z)-7-(6-bromobut-1-en-1-yl)-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 418a (300 mg, 0.57 mmol) was used to obtain Example 418 (3.7 mg) in a 1.5% yield. MS m / z (ESI): 440 [M+1]. +

[0500] 1 H NMR(400MHz,MeOD)δ9.09(s,1H),8.19(s,1H),8.15(d,1H),8.06(m,2H),7.32(s,1H),6.61(d,1H ),5.90(dd,1H),5.37(d,1H),4.93(d,1H),4.07(t,1H),3.50(s,1H),2.85(dd,1H),2.50(d,1H).

[0501] Example 419

[0502] (Z)-4-Amino-12-(3',5'-difluoro-[3,4'-bipyridyl]-6-yl)methyl-9,10,11,12-tetrahydro-13H-azinono[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0503] Step 1: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile 419a (5.73 g, 24.90 mmol), 3,5-difluoro-4-iodopyridine 419b (5 g, 20.75 mmol), Pd(dppf)Cl2 (1.52 g, 2.08 mmol), and K2CO3 (5.74 g, 41.50 mmol) were dissolved in water (50 mL) and 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 12 hours. The reaction was quenched by cooling to air and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 419c (3 g) in a 77.7% yield. MS m / z (ESI): 218 [M+1]. +

[0504] Step 2: Dissolve 419c (2.91 g, 13.40 mmol) in THF (40 mL). Add 2 M LiAlH4 / THF solution (8 mL) at 0°C and stir at 20°C for 3 hours. The reaction is quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, and the resulting residue is purified by reverse phase chromatography using eluent System D to afford 419d (2.15 g) in a 72.5% yield. MS m / z (ESI): 222 [M+1]. +

[0505] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 419 (5.6 mg) was obtained from 419d and 62 g (270 mg, 0.50 mmol) of methyl (Z)-7-(6-bromohex-1-en-1-yl)-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate. The yield was 2.5%. MS m / z (ESI): 498 [M+1]. +

[0506] 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.77(d,1H),8.73(s,2H),8.22(s,1H),8.11(m,1H),7.90(s,1H),7.66(d,1H),7.39(s, 2H),7.19(s,1H),6.54(d,1H),6.00(m,1H),5.06(d,1H),4.47(d,1H),3.43(d,2H),2.12(m,1H),1.79(dq,2H),1.41(d,1H).

[0507] The preparation of the following examples is based on Example 14:

[0508] The preparation of the following examples refers to Example 62:

[0509] Alternatively, the following examples are prepared using the following method:

[0510] Example 427

[0511] 4-amino-12-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-methyl-1,7,9,10,11,12-hexahydro-13H-[1,5]oxazolo[7,8-g]pyrazolo[4,3-c]quinolin-13-one

[0512] By referring to the preparation method of Example 1, methyl 4-amino-2-bromobenzoate 427a (100 mg, 454 μmol) was used to obtain Example 427 (5.2 mg) in a yield of 2.3%. MS m / z (ESI): 516 [M+1] +

[0513] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.36(d,1H),8.16–8.05(m,1H),7.98(d,1H),7.70(d,1H),7.64–7.48(m,2H),7.30(t,2H),5.25(d,1 H),4.75(d,1H),4.59(d,1H),4.52–4.34(m,3H),3.87–3.75(m,1H),3.54–3.36(m,2H),3.26(s,2H),2.03–1.87(m,1H),1.32–1.19(m,1H).

[0514] Example 431

[0515] 4-Amino-12-(5-(2,6-difluorophenyl)pyridin-2-yl)methyl-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolino[7,8-g]quinolin-13(1H)-one

[0516] Referring to the synthesis method of steps 5 to 8 of Example 14, methyl 7-(3-bromopropyl)methyl-4-(3,4-dimethoxybenzyl)amino-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 178e (545 mg, 1 mmol) and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine (242 mg, 1.2 mmol) were used to obtain Example 431 (14 mg) in a 2.8% yield. MS m / z (ESI): 503 [M+1]. +

[0517] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.97(dd,1H),7.66(d,1H),7.57(s,1H),7.55(m,2H),7.30(m,2H),5.43(s,1H),5.25(d,1H),5.06(br s,2H),4.75(d,1H),4.60(d,1H),4.35(d,1H),3.82(d,1H),3.45(m,2H),3.26(m,2H),1.91(m,1H),1.23(d,1H).

[0518] Example 434

[0519] 4-amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0520] Step 1: 2-Cyano-5-fluoropyridine 434a (50 g, 409.5 mmol) was dissolved in DMF (250 mL) and cooled in an ice bath under a nitrogen atmosphere. Na2S (38.35 g, 491.4 mmol) was added portionwise, and the reaction system was stirred at 20°C for 1 hour. The reaction solution was slowly added to 2 L of 1N NaOH solution, and extracted with 2 L of dichloromethane. The layers were separated, and the aqueous phase was collected and the pH was adjusted to 2. A large amount of solid precipitated. After filtration, the filtrate was slurried with isopropanol and water, and the solid was collected to provide 434b (50 g) in an 89.0% yield. MS m / z (ESI): 137 [M+1]. +

[0521] Step 2: 434b (50 g, 367.1 mmol) was dissolved in acetonitrile (250 mL). Under a nitrogen atmosphere, sodium iodide (27.5 g, 183.59 mmol) and ferric chloride (30 g, 183.6 mmol) were added, and the reaction system was stirred at 20°C for 3 hours. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated, and 2 L of ethyl acetate was added for dissolution. 2 L of water was added, and the liquid was separated by extraction. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to obtain a brown solid. The solid was purified by slurrying with ethyl acetate to obtain 434c (10.5 g) in a yield of 21.1%. MS m / z (ESI): 271 [M+1]. +

[0522] Step 3: Under nitrogen, trichloroisocyanuric acid (83.82 g, 360.67 mmol) and ultra-dry potassium fluoride (27.94 g, 480.89 mmol) were added to a reaction flask, followed by anhydrous acetonitrile (130 mL). While stirring, 5,5'-dithiobis(2-cyanopyridine) 434c (6.50 g, 24.04 mmol) was added and stirred at 80°C for 5 h. After the reaction was complete, the mixture was cooled to 20°C, filtered, and the filter cake was washed with anhydrous acetonitrile (20 mL). The filtrate was concentrated under reduced pressure to afford crude product 434d (14.80 g).

[0523] 19 F NMR (400 MHz) δ 136.3 ppm.

[0524] Step 4: To a solution of 434d (14.80 g, crude) in anhydrous dichloromethane (130 mL) was added silver tetrafluoroborate (28.08 g, 144.27 mmol). The reaction suspension was heated to 40°C and stirred for 22 h under nitrogen. After completion of the reaction, the dichloromethane solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was sonicated and filtered. The filter cake was washed with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography using eluent System C to afford 434e (5.5 g, 23.90 mmol) in a two-step yield of 49.7%.

[0525] 1 H NMR (400MHz, CDCl3) δ9.09(d,1H),8.24(dd,1H),7.87(d,1H)ppm;

[0526] 19 F NMR (400 MHz, CDCl3) δ 79.6 ppm.

[0527] Step 5: Dissolve 434e (5.7 g, 24.77 mmol) and 5% palladium on carbon (2.64 g) in ethanol (100 mL). Add 4M hydrogen chloride in methanol (37.15 mL, 148.59 mmol) and stir at 20°C for 16 hours (15 psi hydrogen atmosphere). The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated to obtain a crude product, which was dispersed in ethyl acetate (50 mL) and filtered to afford 434f (5.80 g, 21.43 mmol). Yield: 86.5%. MS m / z (ESI): 271 [M+1]. +

[0528] Step 6: Dissolve 434 g (45.6 g, 316.46 mmol) of methyl 4-oxotetrahydrofuran-3-carboxylate in 500 mL of dichloromethane. Add N,N-diisopropylethylamine (64.50 g, 500.00 mmol) and trifluoromethanesulfonic anhydride (116.80 g, 400.00 mmol) sequentially under an ice bath. Stir the reaction at room temperature for approximately 16 hours. Add 500 mL of water to the reaction mixture, extract with ethyl acetate (400 mL x 2). After extraction, separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by silica gel column chromatography with eluent System B to obtain 434h (75.3 g) in an 86.1% yield.

[0529] Step 7: 3-(Benzyloxy)propan-1-ol 434i (20 g, 120.48 mmol) was dissolved in 400 mL of tetrahydrofuran and sodium hydride (5.78 g, 144.57 mmol, 60% purity) was added under ice-cooling. After stirring for 15 minutes, potassium (bromomethyl)trifluoroborate (24.09 g, 120.00 mmol) was added and the reaction was stirred at room temperature for approximately 16 hours. Potassium bifluoride solution (4.5 M) was added to the reaction solution and stirred at room temperature for 30 minutes. The reaction solution was spin-dried and then added with 2000 mL of hot acetone. The solution was stirred at 80°C for approximately 15 minutes. After hot filtration to remove impurities, the acetone was distilled under reduced pressure until a solid precipitated. Two times the amount of ether was added and the solution was filtered under ice-cooling. The residue was dried to afford 437j (12.5 g) in a 37.9% yield.

[0530] Step 8: Take methyl 4-amino-5-bromo-2-chlorobenzoate 434k (80 g, 302.45 mmol), pinacol diboron (115.21 g, 453.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene (16.77 g, 30.25 mmol), potassium acetate (59.37 g, 604.91 mmol), and palladium acetate (3.40 g, 15.12 mmol) and add 1,4-dioxane (800 mL). Under nitrogen atmosphere, the reaction system is stirred at 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using eluent System B to afford methyl 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 4341 (84 g, 269.60 mmol) in an 89.1% yield. MS m / z (ESI): 312 [M+1]. +

[0531] Step 9: 434l (70.5 g, 226.27 mmol) was added to ethanol (1000 mL) and water (200 mL). Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (62.49 g, 226.27 mmol), sodium carbonate (47.97 g, 452.55 mmol), and bis(triphenylphosphine)palladium(II) chloride (15.88 g, 22.63 mmol) were added. Under a nitrogen atmosphere, the reaction system was reacted at 80°C for 4 hours. The reaction solution was directly concentrated, water was added, stirred for 10 minutes, filtered, and the solid was slurried with ethyl acetate to obtain 434m (49 g, 175.20 mmol) with a yield of 77.4%. MS m / z (ESI): 280 [M+1] +

[0532] Step 10: Dissolve 434m (56.7 g, 202.74 mmol) in dimethyl sulfoxide (25.23 mL), add 2,4-dimethoxybenzylamine (40.68 g, 243.28 mmol) and 1,8-diazobisspiro[5.4.0]undec-7-ene (92.59 g, 608.21 mmol, 90.78 mL), and finally add Carter condensation agent (269.00 g, 608.21 mmol). The reaction system is allowed to react at room temperature for 1 hour. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic phase is separated, dried, concentrated, and slurried with methanol to obtain 434n (43 g, 100.26 mmol) in a 49.5% yield. MS m / z (ESI): 429 [M+1]. +

[0533] Step 11: 434n (2.5 g, 5.83 mmol), ((3-(benzyloxy)propoxy)methyl)trifluoro-L4-borane potassium salt (2.50 g, 8.74 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (424.53 mg, 582.93 μmol), and cesium carbonate (5.70 g, 17.49 mmol) were placed in a sealed tube, 1,4-dioxane (20 mL) and water (2 mL) were added, and the reaction system was reacted at 90°C for 16 hours under a nitrogen atmosphere. The reaction solution was added to saturated brine and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give 434o (1.76 g, 3.07 mmol) in a 52.7% yield. MS m / z (ESI): 573 [M+1] +

[0534] Step 12: 434o (17.1 g, 29.86 mmol) was dissolved in tetrahydrofuran (170 mL) and methanol (170 mL). Acetic acid (10 mL), 10% wt palladium on carbon (8.55 g, 80.34 mmol), and 10% wt palladium hydroxide on carbon (8.55 g, 60.88 mmol) were added. Under a hydrogen atmosphere and a pressure of 60 psi, the reaction system was incubated at 50°C for 20 hours. The reaction solution was filtered and the filtrate was concentrated to obtain 434p (9.64 g, 19.98 mmol) in a 66.9% yield. MS m / z (ESI): 483 [M+1] +

[0535] Step 13: Dissolve 434p (9.64 g, 19.98 mmol) in dichloromethane (100 mL), add carbon tetrabromide (6.63 g, 19.98 mmol) and triphenylphosphine (5.24 g, 19.98 mmol), and react at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using eluent System A to afford 434q (12.64 g, 16.45 mmol) in an 82.4% yield. MS m / z (ESI): 545 [M+1] +

[0536] Step 14: A solution of 434f (4.47 g, 16.50 mmol), 434q (5.00 g, 9.17 mmol), sodium iodide (2.75 g, 18.33 mmol), and cesium carbonate (5.97 g, 18.33 mmol) in acetonitrile (50 mL) was reacted at 80°C for 15 hours. The mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated. The residue was purified by silica gel column chromatography using eluent System C to afford 434r (3.10 g, 4.44 mmol) in a yield of 48.4%. MS m / z (ESI): 699 [M+1]. +

[0537] Step 15: 434r (3.30 g, 4.72 mmol) was dissolved in tetrahydrofuran (20 mL) and methanol (20 mL), and 4 M lithium hydroxide solution (5.90 mL, 23.62 mmol) was added. The mixture was reacted at 50°C for 4 hours. 1 M dilute hydrochloric acid was added to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-((2,4-dimethoxybenzyl)amino)-7-((3-(((5-(pentafluoro-λ 6 -thio)pyridin-2-yl)methyl)amino)propyloxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid 434s (3.00 g, crude). MS m / z (ESI): 685 [M+1] +

[0538] Step 16: Dissolve 434s (3.00 g, 4.38 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.48 g, 6.57 mmol) in N,N-dimethylformamide (15 mL). Add N,N-diisopropylethylamine (1.13 g, 8.76 mmol, 1.53 mL) and react at 25°C for 16 hours. Quench with water and extract with ethyl acetate (80 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent is concentrated. The residue is purified by silica gel column chromatography using eluent System C to afford 434t (2.00 g, 3.00 mmol) in a 47.9% yield. MS m / z (ESI): 667 [M+1]. +

[0539] Step 17: 434t (2.00 g, 3.00 mmol) was dissolved in trifluoroacetic acid (10 mL) and the reaction was incubated at 90°C under a nitrogen atmosphere for 1 hour. The reaction solution was concentrated and the residue was purified by preparative HPLC to afford Example 434 (893 mg, 0.51 mmol) in a 57.6% yield. MS m / z (ESI): 517 [M+1] +

[0540] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.40(dd,1H),7.76(d,1H),7.51(s,1H),7.39(s,1H),6.65(s,2H),5.35(t,2H),5.16(d ,1H),5.01(t,2H),4.72(d,1H),4.53(d,1H),4.43(d,1H),3.78(dt,1H),3.41(m,2H),3.25(m,1H),1.91(q,1H),1.25(m,1H)

[0541] Example 435

[0542] 4-Amino-12-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-3-methyl-1,3,7,8,9,10,11,12-octahydro-13H-[1,5]diamino[7,8-g]furo[3,4-c]quinolin-13-one

[0543] Referring to Example 178, steps 1 to 11, methyl 2-methyl-4-oxotetrahydrofuran-3-carboxylate 184e (4 g, 9.03 mmol) was used to obtain Example 435 (21 mg) in a 0.45% yield via coupling, deprotection, bromination, substitution, hydrolysis, ring closure, and deprotection steps. MS m / z (ESI): 515 [M+1]. +

[0544] 1 HNMR(400MHz,DMSO-d6)δ8.96(d,1H),8.26–8.22(m,1H),7.75(m,1H),7.56(s,1H),7.50(s,1H),7.38(s,1H),7.15(m,2H),6.56(s,2 H),5.47–5.24(m,4H),5.19(m,1H),4.71(m,1H),4.53(m,1H),4.43(d,1H),3.77(d,1H),3.23(d,2H),2.03–1.88(m,2H),1.40(d,3H).

[0545] Example 437

[0546] 4-amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0547] Step 1: 3-(Benzyloxy)propan-1-ol 437a (20 g, 120.48 mmol) was dissolved in 400 mL of tetrahydrofuran. Sodium hydride (5.78 g, 144.57 mmol, 60% purity) was added under ice-cooling. After stirring for 15 minutes, potassium (bromomethyl)trifluoroborate (24.09 g, 120.00 mmol) was added and the reaction was stirred at room temperature for approximately 16 hours. Potassium bifluoride solution (4.5 M) was added to the reaction solution and stirred at room temperature for 30 minutes. The reaction solution was spin-dried and then added with 2000 mL of hot acetone. The solution was stirred at 80°C for approximately 15 minutes. After hot filtration to remove impurities, the acetone was distilled under reduced pressure until solids precipitated. Two times the amount of ether was added, and the solution was filtered under ice-cooling. The residue was dried to afford 437b (12.5 g) in a 37.9% yield.

[0548] Step 2: Dissolve 2-cyanopyridine-5-mercaptopyridine 437c (20 g, 147.06 mmol) in 400 mL of tetrahydrofuran. Add iodine (11.12 g, 44.12 mmol) under ice-cooling. Stir the reaction at room temperature for approximately 16 hours. Add saturated sodium thiosulfate solution to the reaction mixture, stir at room temperature for 30 minutes, and extract with ethyl acetate (400 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System B to afford 437d (15.7 g) in a 79.1% yield. MS m / z (ESI): 271 [M+1]. +

[0549] Step 3: Disperse 437d (15.7 g, 58.15 mmol) in 400 mL of acetonitrile. Add tetraethylammonium chloride (19.19 g, 116.30 mmol) and silver difluoride (134.91 g, 930.40 mmol) under ice. Stir the reaction at room temperature for approximately 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 437e (5.62 g) in a 21.0% yield. MS m / z (ESI): 231 [M+1]. +

[0550] Step 4: Disperse 437e (5.62 g, 24.43 mmol) in 50 mL of methanol and add palladium on carbon (5 g, 10%). Stir the reaction at room temperature under a hydrogen atmosphere for approximately 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 437f (4.61 g) in an 80.1% yield. MS m / z (ESI): 235 [M+1] +

[0551] Step 5: Dissolve 437 g (50 g, 316.46 mmol) of methyl 2-methyl-4-carbonyltetrahydrofuran-3-carboxylate in 500 mL of dichloromethane. Add N,N-diisopropylethylamine (64.50 g, 500.00 mmol) and trifluoromethanesulfonic anhydride (116.80 g, 400.00 mmol) sequentially under ice-cooling. Stir the reaction at room temperature for approximately 16 hours. Add 500 mL of water to the reaction mixture, extract with ethyl acetate (400 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System B to afford 437h (82.5 g) in an 89.9% yield.

[0552] Step 6: Dissolve 437h (40.51 g, 139.69 mmol) and 437i (40.43 g, 130.00 mmol) in 400 mL of dioxane and 100 mL of water. Add (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (4.75 g, 6.50 mmol) and potassium carbonate (53.82 g, 390.00 mmol). Stir the reaction at 100°C under nitrogen for approximately 16 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 437j (24.80 g) in a 65.1% yield. MS m / z (ESI): 294 [M+1]. +

[0553] Step 7: Dissolve 437j (24.80 g, 84.64 mmol) in 200 mL of dimethyl sulfoxide. Add 2,4-dimethoxybenzylamine (26.72 g, 160.00 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (36.48 g, 240.00 mmol), and Carter condensation agent (70.72 g, 160.00 mmol) in that order. Stir the reaction at room temperature under nitrogen for approximately 2 hours. Pour the reaction solution into 2000 mL of water and 300 mL of ethyl acetate. The solid precipitated and was filtered to obtain 437k (26.97 g) in a 72.1% yield. MS m / z (ESI): 443 [M+1]. +

[0554] Step 8: Compound 437k (18.33 g, 41.47 mmol), 437b (12.5 g, 45.62 mol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (4.44 g, 6.10 mol), and sodium carbonate (8.80 g, 83.00 mmol) were dissolved in 200 mL of toluene and 40 mL of water. The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction mixture was extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford compound 437l (16.45 g) in a 67.7% yield. MS m / z (ESI): 587 [M+1]. +

[0555] Step 9: Dissolve 437l (16.45 g, 28.07 mmol) in 200 mL of tetrahydrofuran, 100 mL of methanol, and 3 mL of acetic acid. Add palladium on carbon (5 g, 10%) and palladium hydroxide on carbon (5 g, 10%), and allow the reaction to proceed at 50°C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to yield 437m (10.15 g) in a 72.9% yield. MS m / z (ESI): 497 [M+1] +

[0556] Step 10: Dissolve 437m (10.15 g, 20.46 mmol) and triphenylphosphine (13.40 g, 51.15 mmol) in 200 mL of dichloromethane. Add carbon tetrabromide (16.93 g, 51.15 mmol), and allow the reaction to proceed at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to yield 437n (9.87 g) in an 86.4% yield. MS m / z (ESI): 559 [M+1] +

[0557] Step 11: Disperse 437n (4.00 g, 7.17 mmol), 437f (2.01 g, 8.60 mmol), potassium carbonate (4.95 g, 35.85 mmol), and sodium iodide (2.15 g, 14.34 mmol) in 40 mL of acetonitrile. The reaction was allowed to proceed at 80°C under nitrogen for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to afford 437o (2.21 g) in a 43.3% yield. MS m / z (ESI): 713 [M+1]. +

[0558] Step 12: Dissolve 437o (2.21 g, 3.10 mmol) in 30 mL of methanol and 10 mL of water, and add lithium hydroxide (372 mg, 15.50 mmol). Allow the reaction to proceed at room temperature under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent. 20 mL of water was added to the residue, and the pH was adjusted to 6 with 6N hydrochloric acid. A solid precipitated and was filtered to obtain 437p (1.75 g) in an 80.8% yield. MS m / z (ESI): 699 [M+1] +

[0559] Step 13: Dissolve 437p (300 mg, 0.43 mmol) and N,N-diisopropylethylamine (277 mg, 2.15 mmol) in 20 mL of N,N-dimethylformamide, and add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (327 mg, 0.86 mmol). Allow the reaction to proceed at room temperature under nitrogen for 1 hour. Add 80 mL of water to the reaction mixture, extract with ethyl acetate (40 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System B to afford 437q (210 mg) in a 71.9% yield. MS m / z (ESI): 681 [M+1]. +

[0560] Step 14: Dissolve 437q (100 mg, 0.15 mmol) in 5 mL of trifluoroacetic acid. Incubate the reaction at 80°C under nitrogen for 1 hour. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography using eluent System A to afford 437 (41 mg) in a 52.6% yield. MS m / z (ESI): 531 [M+1] +

[0561] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.40(dd,1H),8.08(d,2H),7.78(d,1H),7.61(d,2H),5.55–5.34(m,3H),5. 17(dd,1H),4.68(ddd,2H),4.46(d,1H),3.83(d,1H),3.53–3.21(m,3H),1.91(s,1H),1.43(d,3H),1.24(d,1H).

[0562] Example 437-P1

[0563] (R)-4-Amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0564] Step 1: 4-((2,4-dimethoxybenzyl)amino)-3-methyl-7-((3-(((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)amino)propoxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid methyl ester 437o (1.91 g, 2.68 mmol) was subjected to chiral preparative HPLC separation to give (R)-4-((2,4-dimethoxybenzyl)amino)-3-methyl-7-((3-(((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)amino)propoxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid methyl ester 437o-P1 (810 mg, t R =2.504 min), yield: 42.4% and (S)-methyl 4-((2,4-dimethoxybenzyl)amino)-3-methyl-7-((3-(((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)amino)propoxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 437o-P2 (760 mg, t R =3.825min), yield: 39.8%.

[0565] Reference Example 437 Steps 12 to 14: Compound (R)-4-amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one 437-P1 (129 mg) was obtained from methyl 4-((2,4-dimethoxybenzyl)amino)-3-methyl-7-((3-(((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)amino)propoxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 437o-P1 (810 mg, 1.14 mmol). Yield: 21.4%. MS m / z (ESI): 531 [M+1]. +

[0566] 1HNMR(400MHz,DMSO-d6)δ9.11(d,1H),8.40(dd,1H),8.08(d,2H),7.78(d,1H),7.61(d,2H),5.55–5.34(m,3H),5 .17(dd,1H),4.68(ddd,2H),4.46(d,1H),3.83(d,1H),3.53–3.21(m,3H),1.91(s,1H),1.43(d,3H),1.24(d,1H).

[0567] Example 437-P2

[0568] (S)-4-Amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0569] Reference Example 437 Steps 12 to 14: Compound (S)-4-amino-3-methyl-12-((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one 437-P2 (115 mg) was obtained from methyl 4-((2,4-dimethoxybenzyl)amino)-3-methyl-7-((3-(((5-(pentafluorosulfanyl)pyridin-2-yl)methyl)amino)propoxy)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 437o-P2 (760 mg, 1.07 mmol). Yield: 20.2%. MS m / z (ESI): 531 [M+1].

[0570] 1 HNMR(400MHz,DMSO-d6)δ9.11(d,1H),8.40(dd,1H),8.08(d,2H),7.78(d,1H),7.61(d,2H),5.55–5.34(m,3H),5 .17(dd,1H),4.68(ddd,2H),4.46(d,1H),3.83(d,1H),3.53–3.21(m,3H),1.91(s,1H),1.43(d,3H),1.24(d,1H).

[0571] Example 484

[0572] 4-amino-12-((5-(bicyclo[1.1.1]pentan-1-yl)pyridin-2-yl)methyl)-9,10,11,12-tetrahydroimidazo[1,5-a][1,5]oxazolo[8,7-g]quinoxalin-13(7H)-one

[0573] Step 1: tert-Butyl N-[(5-bromo-2-pyridyl)methyl]carbamate (1 g, 3.48 mmol), 2-(bicyclo[1.1.1]pentan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 484a (1.01 g, 5.22 mmol, using the known method "Science, 2017, vol. 357, p. 283-286"), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyrrolidone] [[(4,4'-Bis(1,1-dimethylethyl)-2,2'-bipyridyl)iridium]di(hexafluorophosphate)] salt (70 mg, 70 μmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl] nickel(II) dichloride (277 mg, 0.7 mmol) were dissolved in N,N-dimethylformamide (20 mL). The atmosphere was purged with nitrogen three times, and morpholine (455 mg, 5.22 mmol, 0.47 mL) was added. The system was irradiated in a blue light reactor (18W, 456 nm) for 15 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford compound 484b (200 mg) in a 21.0% yield. MS m / z (ESI): 275 [M+1]. +

[0574] Step 2: Dissolve 484b (0.45 g, 1.64 mmol) and dioxane hydrochloride (5 mL) in 1'4-dioxane (5 mL) and react at 25°C for 1 hour. Concentrate to afford 484c (0.28 g, crude product). MS m / z (ESI): 175 [M+1] +

[0575] Referring to the synthesis method of steps 6 to 9 of Example 1304, Example 484 (10 mg) was obtained from 484c (106 mg, 0.61 mmol) and methyl 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 484d (300 mg, 0.55 mmol). Yield: 4.0%. MS m / z (ESI): 455 [M+1]. +

[0576] 1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.41(d,1H),8.07(s,1H),7.91(s,1H),7.67(dd,1H),7.49(d,1H),7.39(d,3H),5.19(d,1H), 4.61(d,1H),4.51(d,1H),4.26(d,1H),3.73(d,1H),3.51(d,2H),3.15(d,2H),2.59(s,1H),2.12(s,5H),1.89(d,1H),1.22(d,1H).

[0577] Example 493

[0578] 4-Amino-8-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7,8,9,10,11,12-hexahydro-13H-[1,5]diazo[7,8-g]imidazo[1,5-a]quinoxalin-13-one

[0579] Step 1: Dissolve 493a (18 g, 103.89 mmol) in 200 mL of tetrahydrofuran (THF). Add sodium hydride (3.59 g, 89.63 mmol, 60% purity) in an ice bath. Stir for 15 minutes, then add potassium (bromomethyl)trifluoroborate (18 g, 89.63 mmol). Allow the reaction to stir at room temperature for approximately 16 hours. Add potassium bifluoride solution (4.5 M) to the reaction solution, stir at room temperature for 30 minutes, spin-dry the reaction solution, add 100 mL of hot acetone, stir at 80°C for approximately 15 minutes, filter out impurities, and vacuum distill the acetone until solids precipitate. Add twice the amount of ether, filter in an ice bath, and dry the residue to obtain 493b (27 g, crude product) in a 100% yield.

[0580] Step 2: Methyl 7-bromo-4-((3,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (4.5 g, 9.55 mmol), 493b (4.48 g, 15.28 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (347.68 mg, 477.40 μmol) and cesium carbonate (9.34 g, 28.64 mmol) were dissolved in 50 mL of dioxane and 10 mL of water and reacted at 100°C under nitrogen for 16 h. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford compound 493c (5.52 g). The crude product was directly used in the next step. MS m / z (ESI): 578 [M+1] +

[0581] Step 3: 493c (5.4 g, 9.35 mmol) was added to a single-necked flask containing methanol (20 mL) and tetrahydrofuran (20 mL). HCl (2 M, 46.74 mL) was added under nitrogen to adjust the pH to 7, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System C to afford 493d (1.1 g, 2.23 mmol) in a 23.8% yield. MS m / z (ESI): 494 [M+1]. +

[0582] Step 4: Dissolve 493d (1.1 g, 2.23 mmol) in dichloromethane (20 mL), purge the mixture with nitrogen three times, and cool to 0°C. Triphenylphosphine (876.85 mg, 3.34 mmol) and carbon tetrabromide (1.11 g, 3.34 mmol) were then added, and the reaction was continued at 25°C for 2 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System C to afford 493e (0.24 g, 431.31 μmol) in a 19.4% yield. MS m / z (ESI): 556 / 558 [M+1]. +

[0583] Step 5: Compound 493e (0.24 g, 431.31 μmol), (5-(trifluoromethyl)pyridin-2-yl)methanamine (151.94 mg, 862.61 μmol), sodium iodide (129.30 mg, 862.61 μmol), and potassium carbonate (119.04 mg, 862.61 μmol) were dissolved in acetonitrile (10 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 80°C for 15 hours. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL x 2), and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System C to afford compound 493f (0.13 g, 199.49 μmol) in a 46.3% yield. MS m / z (ESI): 652 [M+1]. +

[0584] Step 6: Dissolve 493f (0.13 g, 199.49 μmol) in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL). Add lithium hydroxide (33.51 mg, 797.94 μmol). The nitrogen atmosphere is purged three times, and the reaction system is incubated at 25°C for 16 hours. Adjust the pH to 5-6 with 1M dilute hydrochloric acid. Extract with ethyl acetate (50 mL × 3) and wash with saturated brine (50 mL × 2). The organic phase is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to afford 493g (0.08 g, 125.46 μmol) in a 62.9% yield. MS m / z (ESI): 638 [M+1]. +

[0585] Step 7: Dissolve 493 g (0.08 g, 125.46 μmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (95.35 mg, 250.92 μmol) in N,N-dimethylformamide (5 mL). Add N,N-diisopropylethylamine (97.29 mg, 752.76 μmol, 131.12 μL). The reaction system is allowed to react at 25°C for 2 hours. Quench with water, extract with ethyl acetate (80 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent System A to afford 493h (0.076 g, 122.65 μmol), which is used directly in the next step. MS m / z (ESI): 620 [M+1] +

[0586] Step 8: 493h (76.07 mg, 122.76 μmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction system was incubated at 90°C for 0.5 h. The mixture was concentrated and the residue was purified by Pre-HPLC to afford Example 493 (3 mg, 6.39 μmol) in a 5.2% yield. MS m / z (ESI): 470 [M+1] +

[0587] 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.97(s,1H),8.22(dd,1H),8.01(s,1H),7.90(s,1H),7.84(d,1H),7.36(s,2 H),7.32(s,1H),5.16(d,1H),4.41(d,1H),3.80(d,1H),3.55(s,1H),3.25(d,4H),2.33(s,3H),1.36–0.93(m,2H).

[0588] Example 502

[0589] 4-Amino-1,8-dimethyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7,8,9,10,11,12-hexahydro-[1,5]diazacyclononatetraeno[7,8-g]pyrazolo[4,3-c]quinolin-13(1H)-one

[0590] Step 1: A solution of methyl 7-chloro-4-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 502a (800 mg, 1.65 mmol), potassium trifluoro((methyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)amino)methyl)borate 502b (725 mg, 2.47 mmol), cesium carbonate (1.61 g, 4.95 mmol), CataxiumA-Pd-G3 (120.05 mg, 0.16 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 100° C. for 4 hours under nitrogen. The reaction mixture was filtered to remove the solid, and the filtrate was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was concentrated and the residue was purified by silica gel column chromatography to give 502c (602 mg) in a yield of 61.7%. MS m / z (ESI): 592 [M+1] +

[0591] Step 2: To a solution of 502c (602 mg, 1.02 mmol) in methanol (15 mL) was added 4N hydrochloric acid (0.20 mL, 5.00 mmol) and stirred at 20°C for 2 hours. Upon completion of the reaction, the mixture was quenched with sodium bicarbonate solution, extracted with DCM, dried, and spin-dried. Column chromatography afforded 502d (515 mg) in a 99.7% yield. MS m / z (ESI): 508 [M+1] +

[0592] Referring to the synthesis method of steps 5 to 9 of Example 62, Example 502 (6.5 mg) was obtained from 502d (515 mg, 1.01 mmol) in a yield of 1.3%. MS m / z (ESI): 484 [M+1] +

[0593] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.63-8.36(m,3H),8.22-8.11(m,1H),8.01-7.54(m,2H),7.31-7.11(m,1H),6.30-5.91(m,1H),5.71-5.4 4(m,1H),5.41-5.22(m,1H),5.14-4.85(m,2H),4.57-4.41(m,3H),4.34 -4.06(m,2H),3.52–3.17(m,3H),2.58-2.52(m,2H),2.29-2.15(m,1H).

[0594] Example 503

[0595] 4-Amino-1-methyl-12-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1,7,9,10,11,12-hexahydro-13H-[1,5]oxazolo[7,8-g]pyrazolo[4,3-c]quinolin-13-one

[0596] Step 1: 3-(Trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid 503a (5 g, 27.76 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (4.58 g, 36.09 mmol, 3 mL) was added. The mixture was stirred at 25°C for 2 h. Ammonia (7 M, 11.90 mL) in methanol was added and the atmosphere was replaced with nitrogen three times with nitrogen protection. The reaction was stirred at 25°C for 16 h. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the concentrated residue. The mixture was stirred for 15 min and filtered. The filter cake was dehydrated with ethanol (60 mL) and dried under reduced pressure to afford 503b (3.5 g) in a yield of 70.4%.

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.15(s,1H),2.12(s,6H).

[0598] Step 2: 503b (2.2 g, 12.28 mmol) was dissolved in THF (30 mL), the reaction system was cooled to 0°C, and LiAlH4 (2.5 M, 14.7 mL) was slowly added. The atmosphere was replaced with nitrogen three times under nitrogen protection. The reaction was stirred at 25°C for 16 hours. Aqueous sodium hydroxide solution (6 M, 10 mL) was slowly added to the reaction solution, filtered, the filter cake was rinsed with ether (30 mL), the filtrate was collected, filtered, and concentrated under reduced pressure (not spin-dried). Ether (10 mL) was added to the concentrated residue, and ethyl hydrochloride (7 M, 6 mL) was added. The mixture was stirred at 25°C for 15 minutes, filtered, the filter cake was collected, and dried under reduced pressure to give 503c (900 mg). Yield: 44.4%.

[0599] 1 H NMR (400MHz, DMSO-d6) δ3.45(d,2H),2.99(d,2H),1.99(s,6H).

[0600] Step 3: Compounds 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid methyl ester 503d (200 mg, 359 μmol) and 503c (108.51 mg, 538 μmol) were dissolved in MeCN (2 mL). NaI (107.56 mg, 718 μmol) and KCO (198.34 mg, 1.44 mmol) were added sequentially. The atmosphere was purged with nitrogen three times under a nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to afford 503e (90 mg) in a 29.0% yield. MS m / z (ESI): 642 [M+1]. +

[0601] Step 4: 503e (80 mg, 125 μmol) was dissolved in THF (0.6 mL) / MeOH (0.2 mL) / Water (0.2 mL), and LiOH (11.94 mg, 499 μmol) was added. The atmosphere was replaced with nitrogen three times, and nitrogen protection was applied. The reaction was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and water (6 mL) was added to the concentrated residue. The pH was adjusted to 4-5 with 2M hydrochloric acid, filtered, and the filter cake was dried under reduced pressure to obtain 503f (90 mg, crude product), which was used directly in the next step. MS m / z (ESI): 629 [M+1]+

[0602] Step 5: 503f (85 mg, 135 μmol) was dissolved in DMF (456 μL), and DIEA (35.01 mg, 271 μmol, 47 μL) and HATU (76.64 mg, 203 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times under nitrogen protection. The reaction was stirred at 25°C for 5 h. The reaction solution was concentrated under reduced pressure to give 503g (90 mg, crude product).

[0603] Step 6: 503 g (85 mg, 139 μmol) was dissolved in TFA (1 mL), and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 80°C for 0.5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give Example 503 (10 mg). MS m / z (ESI): 460 [M+1] +

[0604] 1 H NMR(400MHz,DMSO-d6)δ13.34(s,2H),8.53(s,1H),7.98(s,1H),7.64(s,1H),4.70(d,1H),4.54(d,1H),4.46(s,2 H),4.10(d,1H),3.84–3.74(m,1H),3.37(dd,3H),3.31–3.09(m,4H),2.05–1.98(m,4H),1.86(q,1H),1.22(d,1H).

[0605] Example 508

[0606] 4-Amino-8-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,7,8,9,10,11,12-octahydro-13H-[1,5]diazacyclononatetraeno[7,8-g]furo[3,4-c]quinolin-13-one

[0607] Step 1: A solution of methyl 7-chloro-4-((2,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 508a (1.0 g, 2.33 mmol), potassium trifluoro((methyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)amino)methyl)borate 508b (1.03 g, 3.50 mmol), cesium carbonate (2.28 g, 7.00 mmol), CataxiumA-Pd-G3 (169.81 mg, 0.23 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 100° C. for 4 hours under nitrogen. The reaction mixture was filtered to remove the solid, and the filtrate was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was concentrated and the residue was purified by silica gel column chromatography to give 508c (289 mg) in a yield of 21.4%. MS m / z (ESI): 580 [M+1] +

[0608] Step 2: 4N hydrochloric acid (0.20 mL, 5.00 mmol) was added to a solution of 508c (550 mg, 0.95 mmol) in methanol (15 mL). The mixture was stirred at 20°C for 2 hours. After completion of the reaction, sodium bicarbonate solution was added to quench the mixture. The mixture was extracted with DCM, dried, and spin-dried. Column chromatography afforded 508d (460 mg) in a 97.8% yield. MS m / z (ESI): 496 [M+1] +

[0609] According to the synthesis method of steps 5 to 9 of Example 62, Example 508 (35.2 mg) was obtained from 508d (460 mg, 0.93 mmol) in an 8.0% yield. MS m / z (ESI): 472 [M+1] +

[0610] 1 H NMR(400MHz,DMSO-d6)δ9.01(br s,1H),8.27(br d,1H),8.05-7.56(m,3H),5.50-5.37(m,2H),5.21-4.86(m,4H),4.85-4 .31(m,2H),3.25-2.96(m,4H),2.93-2.78(m,1H),2.74-2.63(m,4H)ppm.

[0611] Example 510

[0612] 4-amino-12-((5-(bicyclo[1.1.1]pentan-1-yl)pyridin-2-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0613] Referring to the synthesis method of steps 5 to 8 of Example 177, (5-(bicyclo[1.1.1]pentan-1-yl)pyridin-2-yl)methanamine 510a (240 mg, 1.38 mmol) and methyl 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 510b (500 mg, 0.92 mmol) were used to obtain Example 510 (5 mg) in a 1.2% yield. MS m / z (ESI): 457 [M+1]. +

[0614] 1 H NMR(400MHz,DMSO-d6)δ8.40(d,1H),7.66(dd,1H),7.50(s,1H),7.44(d,1H),7.35(s,1H),6.63(s,2H),5.34(s,2H),5.18( d,1H),5.01(s,2H),4.68(d,1H),4.55–4.45(m,2H),4.21(d,1H),3.73(d,1H),3.13(d,3H),2.57(d,1H),2.15–2.04(m,7H).

[0615] Example 514

[0616] 4-Amino-8-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7,8,9,10,11,12-hexahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one

[0617] Step 1: Trimethylaluminum (42.7 mL, 68.3 mmol, 1.6 M) was added dropwise to a solution of zirconocene dichloride (1.20 g, 4.11 mmol) in dichloromethane (34 mL) at -70°C under nitrogen. Deionized water (185 mg, 10.3 mmol) was then added dropwise to the reaction mixture. The reaction mixture was stirred at -70°C for 0.5 hour, then warmed to room temperature and stirred for 0.5 hour. The reaction mixture was cooled to -70°C, and tert-butyl-dimethyl-4-alkynyloxysilane (4.06 g, 20.47 mmol) was added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was cooled to -70°C, and a solution of iodine (10.4 g, 40.98 mmol) in tetrahydrofuran (28 mL) was added dropwise to the reaction mixture. The mixture was stirred at -70°C for 0.5 hour, then warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly quenched with sodium thiosulfate solution and extracted with ether (100 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography to afford 514b (5.30 g) in a 76.1% yield.

[0618] Step 2: n-Butyl lithium (5.82 mL, 2.5 M) was added dropwise to a solution of 514b (3.30 g, 9.70 mmol) and 2,2'-bipyridine (76 mg, 0.48 mmol) in tetrahydrofuran (32 mL) at -70°C under nitrogen. The reaction mixture was stirred at -70°C for 0.5 h. Triisopropyl borate (2.74 g, 14.55 mmol) was added dropwise to the reaction mixture, which was then heated to 0°C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (100 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford 514c (1.50 g) in a 59.9% yield. MS m / z (ESI): 259 [M+1] +

[0619] Step 3: Methyl 7-bromo-4-[(3,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinoxaline-8-carboxylate (2.11 g, 4.47 mmol), 514c (1.50 g, 5.81 mmol), sodium carbonate (947 mg, 8.94 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (327 mg, 0.45 mmol) were dissolved in water (3 mL) and dioxane (20 mL). The atmosphere was purged with nitrogen three times and stirred at 90°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to afford 514d (2.10 g) in a 77.7% yield. MS m / z (ESI): 605 [M+1]. +

[0620] Step 4: Dissolve 514d (2.00 g, 3.31 mmol) and tetrabutylammonium fluoride (6.61 mL, 1 M) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford 514e (1.20 g) in a 73.9% yield. MS m / z (ESI): 491 [M+1] +

[0621] Step 5: Dissolve 514e (1.00 g, 2.04 mmol) and platinum dioxide (93 mg, 0.41 mmol) in methanol (20 mL) and acetic acid (2.5 mL). The reaction mixture was stirred at room temperature for 48 hours. After the reaction, the reaction mixture was filtered to remove solids, concentrated, and the residue was purified by silica gel column chromatography to afford 514f (860 mg) in 85.6% yield. MS m / z (ESI): 493 [M+1] +

[0622] Step 6: Carbon tetrabromide (1.02 g, 3.09 mmol) in dichloromethane (3 mL) was added dropwise to a solution of 514f (760 mg, 1.54 mmol) and triphenylphosphine (809 mg, 3.09 mmol) in dichloromethane (8 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to afford 514f (660 mg) in a 77.0% yield. MS m / z (ESI): 555 [M+1] +

[0623] Referring to the synthesis method of Example 510, Example 514 (20 mg) was obtained from 514 g (200 mg, 0.36 mmol) with a yield of 11.8%. MS m / z (ESI): 469 [M+1] +

[0624] 1 H NMR(400MHz,MeOD)δ9.25(s,1H),8.89(s,1H),8.35(s,1H),8.22(d,1H),8.16(dd,1H),7.74(d,1H),7.53(s,1H),5.22(d,1H),4.7 1(d,1H),3.51(dd,1H),3.20–3.12(m,1H),2.87(dd,1H),2.57(dd,1H),2.19(t,1H),1.90–1.83(m,1H),1.56(dd,3H),1.16(d,3H).

[0625] Example 514-P1 & 514-P2

[0626] Example 514 (42 mg, 0.09 mmol) was separated by chiral preparative HPLC to give (R)-4-amino-8-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7,8,9,10,11,12-hexahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one 514-P1 (15 mg) in a 35.7% yield; and (S)-4-amino-8-methyl-12-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7,8,9,10,11,12-hexahydro-13H-azo[4,3-g]imidazo[1,5-a]quinoxalin-13-one 514-P2 (15 mg) in a 35.7% yield.

[0627] 514-P1(t R :1.902min): 1 H NMR(400MHz,MeOD)δ9.25(s,1H),8.89(s,1H),8.35(s,1H),8.22(d,1H),8.16(dd,1H),7.74(d,1H),7.53(s,1H),5.22(d,1H),4 .71(d,1H),3.51(dd,1H),3.20–3.12(m,1H),2.87(dd,1H),2.57(dd,1H),2.19(t,1H),1.86(m,1H),1.56(dd,3H),1.16(d,3H).

[0628] 514-P2(t R :3.117min): 1 H NMR(400MHz,MeOD)δ9.25(s,1H),8.89(s,1H),8.35(s,1H),8.22(d,1H),8.16(dd,1H),7.74(d,1H),7.53(s,1H),5.22(d,1H),4 .71(d,1H),3.51(dd,1H),3.20–3.12(m,1H),2.87(dd,1H),2.57(dd,1H),2.19(t,1H),1.86(m,1H),1.56(dd,3H),1.16(d,3H).

[0629] Example 555

[0630] 4-Amino-12-(but-2-yn-1-yl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0631] Referring to the synthesis method of Example 173, Example 555 (38 mg) was obtained from methyl 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 555a (500 mg, 0.92 mmol) and prop-1-yn-1-amine (101 mg, 1.83 mmol) in an 11.8% yield. MS m / z (ESI): 352 [M+1]. +

[0632] 1 H NMR(400MHz,DMSO-d6)δ7.51(s,1H),7.38(s,1H),6.99(s,2H),5.35(t,2H),5.02(d,2H),4.72(dt,2.6Hz,1H), 4.62–4.50(m,2H),3.83(dq,1H),3.73(d,1H),3.47–3.38(m,2H),3.22(t,1H),2.00–1.78(m,4H),1.23(d,1H).

[0633] Example 556

[0634] 4-Amino-1-methyl-12-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1,7,9,10,11,12-hexahydro-13H-[1,5]oxazolo[7,8-g]pyrazolo[4,3-c]quinolin-13-one

[0635] Step 1: 2-But-2-ynyloctadiene-1,3-dione 556a (10 g, 50.20 mmol) was dissolved in DCM (100 mL), and NH2NH2 (2.41 g, 75.30 mmol, 2.5 mL) was added. The atmosphere was replaced with nitrogen three times, and nitrogen protection was turned on. The reaction was stirred at 25°C for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ether (60 mL). The filtrate was concentrated under reduced pressure (note that it could not be spin-dried). Ether (20 mL) was added to the concentrated residue, and then a solution of ethyl acetate (7 M) hydrochloric acid (20 mL) was added. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain 556b (1.5 g) with a yield of 28.3%.

[0636] 1 H NMR (400MHz, DMSO-d6) δ8.58(s,3H),3.59(dq,2H),1.82(t,3H).

[0637] Step 2: Methyl 7-(3-bromopropoxymethyl)-4-[(2,4-dimethoxyanilino)methyl]-1-methylpyrazolo[4,3-c]quinoline-8-carboxylate 556c (500 mg, 781 μmol) and 556b (123.57 mg, 1.17 mmol) were dissolved in MeCN (2 mL). KCO (431.40 mg, 3.12 mmol) and NaI (233.94 mg, 1.56 mmol) were added sequentially. The atmosphere was purged with nitrogen three times under a nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC to afford 556d (120 mg) in a 25.6% yield. MS m / z (ESI): 546 [M+1]. +

[0638] Step 3: 556d (120 mg, 220 μmol) was dissolved in THF (3 mL) / MeOH (1 mL) / Water (1 mL), and LiOH (21.07 mg, 880 μmol) was added sequentially. The atmosphere was replaced with nitrogen three times, and nitrogen protection was applied. The reaction was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and water (6 mL) was added to the concentrated residue. The pH was adjusted to 4-5 with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 556e (120 mg, crude). MS m / z (ESI): 533 [M+1] +

[0639] Step 4: 556e (110 mg, 207 μmol) was dissolved in DMF (2 mL), and DIEA (80.23 mg, 621 μmol, 108 μL) and HATU (156.13 mg, 414 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and nitrogen protection was applied. The reaction was stirred at 25°C for 5 hours. The reaction solution was concentrated under reduced pressure to obtain 556f (120 mg, crude). MS m / z (ESI): 514 [M+1] +

[0640] Step 5: 556f (110 mg, 214 μmol) was dissolved in TFA (1 mL) and the reaction was stirred at 80°C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to afford Example 556 (20 mg) in a 23.6% yield. MS m / z (ESI): 364 [M+1] +

[0641] 1H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.40(dd,1H),7.78(d,1H),7.67(s,1H),7.61(s,1H),5.46(t,2H),5.22–5 .03(m,3H),4.75(d,1H),4.61(d,1H),4.46(d,1H),3.83(dd,1H),3.31(s,3H),2.03–1.85(m,1H),1.25(d,2H).

[0642] Example 557

[0643] 4-Amino-12-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3,7,9,10,11,12-hexahydrofuro[3,4-c][1,5]oxazolo[7,8-g]quinolin-13(1H)-one

[0644] Referring to the synthesis method of Example 173, Example 557 (35 mg) was obtained from methyl 7-((3-bromopropoxy)methyl)-4-(3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 557a (500 mg, 0.92 mmol) and (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanamine hydrochloride 557b (182 mg, 1.10 mmol) in an 8.5% yield. MS m / z (ESI): 448 [M+1]. +

[0645] 1 H NMR(400MHz,DMSO-d6)δ7.98(s,2H),7.60(s,1H),7.47(s,1H),5.45(s,2H),5.08(d,2H),4.66(d,1H ),4.53(d,1H),4.06(d,1H),3.75(d,1H),3.20–2.93(m,5H),2.01(q,5H),1.85(d,1H),1.20(d,1H).

[0646] Example 638

[0647] (Z)-4-amino-11-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3,9,10,11-tetrahydronaphthyridin[3,4-g]furo[3,4-c]quinoxalin-12(1H)-one

[0648] Referring to the first to fifth steps of Example 331, methyl 7-chloro-4-((2,4-dimethoxyphenyl)amino)-1,3-dihydrofuro[3,4-c]quinoxaline-8-carboxylate 178c (560 mg, 1.31 mmol) and tert-butyl 3-alkyn-1-yl((5-(trifluoromethyl)pyridin-2-yl)methyl)amine carbonate 638b (428 mg, 1.31 mmol) were reacted with hydrogenation and deprotection to afford 638e (250 mg) in a 30.6% yield. MS m / z (ESI): 623 [M+1]. +

[0649] Step 6: Dissolve 638e (280 mg, 0.38 mmol) and lithium hydroxide (28 mg, 1.16 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction system was incubated at 50°C for 4 hours. The mixture was concentrated. The residue was purified by reverse-phase column chromatography using eluent System A to afford 638f (170 mg) in a 73.4% yield. MS m / z (ESI): 609 [M+1] +

[0650] Step 7: 638f (150 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol), and N,N-diisopropylethylamine (159 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction system was reacted at 20°C for 2 hours. Ammonium chloride was added to quench the reaction. Then, 20 mL of water and 200 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 20 mL of saturated brine, then dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent System A to obtain 638g (100 mg) in a 67.7% yield. MS m / z (ESI): 591 [M+1]. +

[0651] Step 8: Dissolve 638 g (40 mg, 0.067 mmol) in trifluoroacetic acid (2 mL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 90°C for 0.5 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography using eluent System A to afford Example 638 (16.3 mg) in a 55.2% yield. MS m / z (ESI): 441 [M+1]. +

[0652] 1H NMR(400MHz,DMSO-d6)δ8.95(m,1H),8.23(m,1H),7.69(s,1H),7.62(m,1H),7.47(s,1H),6.68(m,1H),5.9 0(m,1H),5.42(m,2H),5.13-5.05(m,3H),4.62(m,1H),3.75(m,1H),3.36(m,2H),2.72(m,1H),2.38(m,1H).

[0653] Example 688

[0654] (Z)-4-Amino-11-((6-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)-10,11-dihydroazo[4,3-g]imidazo[1,5-a]quinoxalin-12(9H)-one

[0655] Step 1: 5-Bromo-6-methylpyridine-2-carbonitrile 688a (8.00 g, 40.60 mmol), cuprous iodide (11.60 g, 60.90 mmol), and methyl 2,2-difluoro-2-fluorosulfonylacetate (23.40 g, 121.81 mmol) were dissolved in N,N-dimethylformamide (50 mL). The mixture was purged with nitrogen three times and stirred at 100°C for 16 hours. The reaction mixture was filtered to remove solids, and the filtrate was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to afford 688b (6.10 g) in 80.7% yield. MS m / z (ESI): 187 [M+1] +

[0656] Step 2: Lithium aluminum tetrahydride (5.37 mL, 2.5 M) was added dropwise to a solution of 688b (2.00 g, 3.31 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction mixture was stirred in an ice bath for 1 hour. Upon completion of the reaction, the mixture was quenched with sodium sulfate decahydrate and the solid was removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford 688c (460 mg) in an 18.0% yield. MS m / z (ESI): 191 [M+1] +

[0657] Referring to the synthesis method of steps 6 to 9 of Example 62, Example 688 (15 mg) was obtained from 688c (200 mg, 1.04 mmol) in a yield of 3.2%. MS m / z (ESI): 453 [M+1] +

[0658] 1H NMR(400MHz,MeOD)δ9.27(s,1H),8.31(d,2H),8.06(d,1H),7.48(d,1H),7.38(s,1H),6.60(m,1H),5. 95(m,1H),5.15(d,1H),4.64(d,1H),4.01(t,1H),3.44(d,1H),2.82(m,1H),2.69(d,3H),2.47(d,1H).

[0659] Biological test evaluation

[0660] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0661] Test Example 1: Determination of the ability of the compounds of the present invention to enhance the thermal stability (melting temperature) of the PRMT5 / MEP50-MTA protein complex.

[0662] 1 Experimental Purpose: The purpose of this test is to measure the ability of compounds to enhance the thermal stability of the PRMT5 / MEP50-MTA protein complex and increase the protein melting temperature.

[0663] 2 Experimental instruments: Quantitative PCR instrument (Quantstudio6 Flex) was purchased from Life Science; pipettes were purchased from Eppendorf or Rainin.

[0664] 3 Experimental reagents and consumables: PRMT5 / MEP50 protein was prepared by Via Biotech; HEPES was purchased from Thermo Fisher, catalog number 15630080; DTT was purchased from Sigma, catalog number 43816-10ml; sodium chloride was purchased from Invitrogen, catalog number AM9760G; Protein Thermal Shift TM Dye Kit was purchased from Thermo Fisher with a catalog number of 4461146; methylthioadenosine (MTA) was purchased from Sigma with a catalog number of D5011.

[0665] 4 Experimental Methods: This study characterizes the ability of compounds to enhance the thermal stability of the PRMT5 / MEP50-MTA protein complex by measuring the change in melting temperature (Tm) of the complex before and after compound binding using the thermal shift method. A solution containing 50 mM HEPES, 10 mM DTT, 2 μM MTA, SYPRO Orange, and 250 mM NaCl was prepared as the experimental buffer. Human PRMT5 / MEP50 protein was added to a final concentration of 2 μM and incubated at room temperature for 30 minutes. The reaction mixture was aliquoted into 8 PCR tube strips, 19.5 μL per tube. 0.5 μL of test compound or DMSO was added, resulting in a total reaction volume of 20 μL and a final compound concentration of 8 μM. A 2.5% DMSO control was used as the vehicle. After incubation at room temperature for 10 minutes, the PCR tube was placed in a PCR instrument, and the melt curve function was selected to detect the melting temperature of the PRMT5 / MEP50-MTA protein complex in different treatment groups (heating from 25°C to 95°C, 0.03°C / s).

[0666] 5. Experimental Data Processing Method: Import the PCR instrument experimental data file into the thermal shift software to obtain the melting temperature (Tm) of each treatment group and subtract the Tm of the DMSO solvent control group to obtain the melting temperature change value (ΔTm) as shown in the following table:

[0667] 6 Experimental conclusion: The compound of the present invention has good binding ability with PRMT5 / MEP50-MTA protein.

[0668] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

[0669] 1 Experimental purpose: The purpose of this test case is to measure the inhibitory effect of compounds on the proliferation activity of HCT116 wild-type and HCT116 MTAP knockout cells.

[0670] 2 Experimental instruments: centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin).

[0671] 3 Experimental reagents: HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega, catalog number G7573; McCoy`5A was purchased from Gibco, catalog number 12330031; FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023; trypsin was purchased from Gibco, catalog number 25200056; cell culture plates were purchased from Corning, catalog number 3610.

[0672] 4 Experimental Methods: When HCT116 and MTAP Knockout HCT116 cells were cultured to an appropriate cell density in McCoy'5A medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete medium. The cell suspension was plated into a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium. A solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and continued to be cultured in a 37°C, 5% CO2 incubator for 72 to 240 hours. Then, CellTiter-Glo solution was added, the plates were shaken to mix evenly, and the plates were incubated in the dark for 10 to 30 minutes. The plates were read using a Synergy H1 or Envision microplate reader.

[0673] 5 Experimental data processing method: The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.

[0674] 6 Experimental Conclusion: The compounds shown in the present invention have good proliferation inhibitory activity against HCT116 MTAP knockout cells and have good selectivity for wild-type HCT116 cells.

[0675] Test Example 3: Pharmacokinetics of the compounds of the present invention in mice (plasma) after oral administration

[0676] 1. Study purpose: Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.

[0677] 2 Experimental plan

[0678] 2.1 Test drugs: Compounds of the present invention, homemade;

[0679] 2.2 Experimental animals: Balb / c male mice were purchased from Shanghai JXJ Laboratory Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006, No. 311620400001794).

[0680] 2.3 Drug preparation: Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80).

[0681] Weigh 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 cps), dissolve it in 1000 mL of purified water, and add 10 g of Tween 80. Mix well to form a clear solution.

[0682] 4 mg of the example compound was weighed and dissolved in the solution, shaken, broken with a cell disrupter for 1 min, and ultrasonicated for 10 minutes to obtain a suspension solution with a concentration of 3 mg / mL.

[0683] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the dosage. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added, vortexed and sonicated for 2 minutes to completely dissolve. Finally, 85% PBS was added, vortexed and sonicated for 5 minutes, and filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0684] 2.4 Administration: Three male Balb / c mice were fasted overnight and administered PO at a dose of 30 mg / kg in a volume of 10 mL / kg.

[0685] 2.5 Sample collection: 0.04 mL of blood was collected from the orbit at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was placed in an EDTA-2K tube and centrifuged at 6000 rpm at 4°C for 6 min to separate the plasma, which was then stored at -20°C. Food was consumed 4 h after administration.

[0686] 3. Determination results: The final determination results were obtained using the LCMS / MS method, which showed that the example compound had a higher oral exposure.

[0687] Test Example 4: Pharmacokinetics of the compounds of the present invention in rats (plasma) after oral administration

[0688] 1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 5 mg / kg.

[0689] 2 Experimental plan

[0690] 2.1 Test Drugs: Solvent formulation: 0.5% CMC-Na (1% Tween 80); homemade in the examples of the present invention.

[0691] 2.2 Experimental Animals: Three male Sprague-Dawley rats per group. Shanghai Bikeway Biotechnology Co., Ltd., Animal License No. (SCXK (Shanghai) 2018-0006, No. 20180006037467).

[0692] 2.3 Administration: 3 male SD rats per group were fasted overnight and administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0693] 2.4 Sample collection: Before and after administration, rats were given blood (0.2 mL) from the jugular vein at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The blood was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma. The plasma was stored at -80°C and fed 4 hours after administration.

[0694] 2.5 Sample processing

[0695] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed and centrifuged at 3500 × g for 5-20 minutes.

[0696] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0697] 2.6 Liquid phase analysis

[0698] Liquid phase conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0699] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0700] ●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

[0701] Flow rate: 1.0 mL / min Elution time: 0-4.0 minutes, eluent as follows:

[0702] 3 Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2 to obtain the results of the rat pharmacokinetic experiment. The results are shown in the following table:

[0703] 4 Experimental conclusion: Oral administration of 5 mg / kg dose, the example compounds of the present invention showed good metabolic properties, exposure AUC and maximum blood concentration C maxAll performed well.

[0704] Test Example 5: hERG potassium channel inhibitory activity test

[0705] 1. Study Purpose: The purpose of the test case is to measure the inhibitory ability of the compound on the activity of hERG potassium ion channel.

[0706] 2 Experimental instruments and reagents:

[0707] 2.1 Reagents

[0708] 2.2 Instruments and consumables

[0709] 3 Experimental methods

[0710] 3.1 Cell Culture: CHO cells stably expressing the hERG potassium channel (CHO-hERG) were obtained from Sophion Biosciences (Ballerup, Denmark) and cryopreserved at Shanghai WuXi AppTec. CHO-hERG cells were cultured and passaged in Ham's F-12 medium supplemented with 1× GlutaMAX, 10% fetal bovine serum, 100 μg / mL G418, and 100 μg / mL hygromycin B in 5% CO2 at 37°C.

[0711] 3.2 Preparation of Extracellular and Intracellular Fluids: Extracellular fluid was prepared monthly and stored in 1L aliquots. Intracellular fluid was prepared every three months and stored frozen at -20°C. Thaw the intracellular fluid in a 37°C water bath before the start of the experiment and place it in an ice bath until use.

[0712] 3.3 Compound Preparation: The positive control drug, amitriptyline hydrochloride, and the compounds were prepared in 100% DMSO (Sigma-Aldrich, D2650) to a 10 mM or 30 mM stock solution. Prior to the experiment, the stock solutions of the test compounds were diluted with DMSO to 1000-fold or 333-fold the respective test concentrations, and then further diluted 1000-fold or 333-fold with extracellular fluid to the desired concentrations.

[0713] 3.4 Preliminary cell preparation: CHO-hERG cells used in the experiment were cultured for at least two days. When the cell density reached above 75%, the cells were digested with TrypLE, resuspended in extracellular solution, and centrifuged. After removing the supernatant, 2 mL of extracellular solution was added to resuspend the cells for later use.

[0714] 3.4 Experimental data processing: In data processing, when judging the blocking effect on hERG, the peak value of the tail current and its baseline are corrected. The inhibition rate of the tail current is used to represent the effect of each compound at different concentrations. IC 50The values ​​are obtained by fitting the Hill equation: I / Icontrol=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0715] Top: maximum effect; Bottom: minimum effect; Hillslope: slope; X: test sample concentration.

[0716] IC 50 : The half-maximal inhibitory concentration of the test compound on hERG. If the inhibition rate at the lowest concentration exceeds half inhibition or the inhibition rate at the highest concentration does not reach half inhibition, the corresponding IC 50 Below minimum concentration or IC 50 The value is greater than the highest concentration.

[0717] 4 Experimental conclusion: The superior compounds of the present invention have inhibitory activity on cardiac hERG potassium ion channels (IC 50 ) greater than 5 μM, even greater than 15 μM, especially the inhibitory activity (IC 50 ) greater than 30 μM, which can avoid the cardiac toxicity at high doses.

[0718] Test Example 6: In vivo pharmacodynamic study of the compound of the present invention in a subcutaneous transplant tumor model of human lung cancer cell line LU99 nude mice

[0719] 1. Study purpose: To evaluate the in vivo efficacy of the compound in the subcutaneous transplant tumor model of nude mice with human lung cancer cell line LU99.

[0720] 2 Experimental instruments and reagents

[0721] 2.1 Instruments: Refrigerator (BCD-268TN, Haier); Biosafety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); Clean Bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.); Electric pipette assistant (Easypet 3, Eppendorf); Constant temperature water bath (HWS-12, Shanghai Yiheng Science); CO2 incubator (Thermo-311, Thermo); Centrifuge (Centrifuge 5720R, Eppendorf); Automatic cell counter (Countess II, Life Sciences) Technologies); vernier caliper (CD-6" AX, Mitutoyo, Japan); cell culture flasks (T25 / T75 / T225, Corning); electronic balance (CPA2202S, Sartorius); electronic balance (BSA2202S-CW, Sartorius); ultrasonic cleaner (115F0032, Shanghai Kedao); water purifier (Pacific TII, Thermo); magnetic stirrer (08-2G, Chijiu).

[0722] 2.2 Reagents: RPMI-1640 medium (22400-089, Gibco); fetal bovine serum (FBS) (A5669701, Gibco); phosphate-buffered saline (PBS) (10010-023, Gibco); Matrigel (356234, Corning); sodium carboxymethylcellulose (30036365, Sinopharm Group); Tween-80 (30189828, Sinopharm Group).

[0723] 3 Experimental operation and data processing

[0724] 3.1 Animals: BALB / c nude mice, 6-8 weeks old, female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0725] 3.2 Cell culture and cell suspension preparation

[0726] a) Take out a strain of LU99 cells from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640 + 10% FBS), and place the resuscitated cells in a cell culture flask in a CO2 incubator (incubator temperature: 37°C, CO2 concentration: 5%).

[0727] b) Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0728] c) Cells in the exponential growth phase were collected and counted using an automatic cell counter. Based on the count results, the cells were resuspended in PBS and mixed with Matrigel in a 1:1 ratio to a concentration of 5 × 10 7 cells / mL and placed in an ice box until use.

[0729] 3.3 Cell seeding

[0730] a) Before inoculation, nude mice were marked with disposable ear tags for both rats and mice;

[0731] b) Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any air bubbles, and place the syringe on an ice pack until ready to use.

[0732] c) Secure the nude mouse with your left hand and disinfect the right side of the mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. After 30 seconds, begin inoculation.

[0733] d) The nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0734] 3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0735] a) Based on tumor growth, the tumor was measured and the size of the tumor was calculated on days 9-12 after inoculation. Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2;

[0736] b) Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0737] c) According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once or twice a day; administration cycle: 28 days; solvent: 0.5% CMC-Na (1% Tween 80)).

[0738] d) Tumors were measured and weighed twice a week after the start of administration of the test drug.

[0739] e) Euthanize the animals after the experiment.

[0740] f) Data were processed using Excel or other software. Calculation of compound tumor inhibition rate (TGI) (%): If tumors did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the start of dosing for that treatment group) / (average tumor volume at the end of treatment for the solvent control group - average tumor volume at the start of treatment for the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the start of dosing for that treatment group) / average tumor volume at the start of dosing for that treatment group] × 100%.

[0741] 4 Experimental conclusions:

[0742] The advantageous compounds of the present invention have a tumor inhibition rate (TGI) greater than 80% or even greater than 90% at low doses, showing a significant tumor growth inhibition effect. At high doses, the compounds have a tumor inhibition rate (TGI) greater than 100% or even greater than 150%, showing a significant tumor regression effect.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Condensed cycloalkyl, 6-10 membered condensed heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O)-、-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, substituted by one or more substituents; preferably -CR aa R bb -、-C(O)-、-S(O) m1 -or-NR cc -; L2 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-12 Aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR f ) or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-10 Aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Or, R1 and R a , R b or R c Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1- 3-Hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h 、-C(=NR i )NR g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f Preferably, the substituted amine group is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents; Alternatively, any two R3 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 4-Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R a , R b , R c , R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Or, R a With R b Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2-6 Alkenylene or C 2-6 Alkyne, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R g , R h , R i and R j are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Or, R g With R h Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1- 6-Hydroxyalkyl, cyano-substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1- 3 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Selected from 3. A compound represented by general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: M1 is selected from -N- or -CR a -; M a Selected from CR 2a NR 2a or N; M b Selected from CR 2b NR 2b or N; Or, R 2a With R 2b Link to form ring A; Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R 2c replaced by; Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; L2 is selected from a bond, -(CR aa R bb ) m2 -, -(CR aa R bb ) m2 C(O)-, -(CR aa R bb ) m2 NR cc C(O), -(CR aa R bb ) m2 S(O) m1 -, or -(CR aa R bb ) m2 NR cc -; L5 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; L6 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; L7 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 2a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 2b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents; R 9a and R 9b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R g and R h are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R N is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1- 3 haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; y is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; m2 is selected from 0, 1 or 2; n2 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2, 3 or 4; n9 is selected from 0, 1, 2, 3 or 4; n10 is selected from 0, 1, 2, 3 or 4.

4. The compound according to claim 1 or 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (III-E), its stereoisomer or a pharmaceutically acceptable salt thereof: L6 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably from a bond, -O-, -S-, -C(O), -NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6- 12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; more preferably -O-, -S-, -C(O), -NR N -、C 1-3 Alkylene or C 2-4 Alkenylene, the C 1-3 Alkylene and C 2-4 Alkenylene, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; L7 is selected from a bond, -O(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 O-、-S(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 S-、-C(O)(CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 C(O)-、-NR N (CR 9a R 9b ) n10 -、-(CR 9a R 9b ) n10 NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-, =CR 9a R 9b , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably from a bond, -O-, -S-, -C(O), -NR N -、-C(O)NR N -、-NR N C(O)-、-S(O)2NR N -、-NR N S(O)2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6- 12 Arylene or 5-12 membered heteroarylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; n8 is selected from 0, 1, 2, 3 or 4; preferably 1, 2 or 3; n9 is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2; n10 is selected from 0, 1, 2, 3 or 4; Ring A, Ring B, L2, M1, M3, R c , R2, R3, x and y are as defined in claim 1.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (IV-E), its stereoisomer or a pharmaceutically acceptable salt thereof: M5 is selected from N or CR 3a ; M6 is selected from N or CR 3b ; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 3a , R 3b , R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1- 6 alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents; R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h or -C(=NR i )NR g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents; L5, L6, L7, n8 and n9 are defined as in claim 3; Ring A, M1, M3, R c , R2 and x are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from 3-12 membered heterocyclic group or 5-12 membered heteroaryl group; preferably 5 membered heterocyclic group, 6 membered heterocyclic group, 5 membered heteroaryl group or 6 membered heteroaryl group; more preferably 7. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from 3-6 membered heterocyclyl and phenyl or 3-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably Or, Ring B is selected from 6-14 membered tricyclic heterocyclic group; preferably 6-14 membered tricyclic spiro heterocyclic group or 6-14 membered tricyclic fused heterocyclic group; more preferably 8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (VI-A) or (VI-B): n11 is selected from 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 or R 2c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 4-Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Cycloalkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 The cycloalkyl group is substituted by one or more substituents; R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 alkyl; Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1- 3-deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1- 3-deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl.

10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R3 and R 3c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl or -SF5, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 3a , R 3b , R 3d and R 3e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-Hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl group and the 5- to 12-membered heteroaryl group may be substituted by one or more substituents.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

12. A compound represented by the general formula (AI), its stereoisomer or a pharmaceutically acceptable salt thereof: R' is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl; R is selected from halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or R" is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; The compound represented by the following general formula (A-II) is preferred: Preferably, the compound represented by general formula (A-II) is further represented by general formula (IV-EI), general formula (IV-AI) or general formula (IV-BI): Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 2,4-dimethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; M1, M a 、M b , Ring A, Ring B, L2, L5, L6, L7, R a , R b , R c , R3, n8, n9, x and y are as described in any one of claims 3 to 7; M5, M6, R 3a , R 3b , R 3c , R 3d , R 3e , R5 and n11 are as described in claim 5 or 8.

13. The compound according to claim 12, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

14. A method for preparing a compound represented by general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (AI) is reacted in the presence of a condensing agent and a base to obtain a compound represented by the general formula (A-II), and the protecting group is further removed to obtain a compound represented by the general formula (A); Preferably, the method is a method for preparing a compound represented by general formula (IV-E), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (IV-EI) is reacted in the presence of a condensing agent and a base to obtain a compound represented by the general formula (IV-E-II), and the protecting group is further removed to obtain a compound represented by the general formula (IV-E); Or, the method is a method for preparing a compound represented by general formula (VI-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (VI-AI) is reacted in the presence of a condensing agent and a base to obtain a compound represented by the general formula (VI-A-II), and the protecting group is further removed to obtain a compound represented by the general formula (VI-A); Or, the method is a method for preparing a compound represented by general formula (VI-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (VI-BI) is reacted in the presence of a condensing agent and a base to obtain a compound represented by the general formula (VI-B-II), and the protecting group is further removed to obtain a compound represented by the general formula (VI-B); Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl or p-methoxyphenyl; M1, M a 、M b , Ring A, Ring B, L2, L5, L6, L7, R a , R b , R c , R3, n8, n9, x and y are as defined in any one of claims 3 to 7; M5, M6, R 3a , R 3b , R 3c , R 3d , R 3e , R5 and n11 are as defined in claim 5 or 8.

15. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound according to any one of claims 1 to 11, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a PRMT5 inhibitor drug.

17. Use of the compound according to any one of claims 1 to 11, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating cancer.

18. The use according to claim 17, characterized in that The cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.